JP2010529200A - Novel heterocyclic H3 antagonist - Google Patents

Abstract

Formula (I) {wherein W, X, Y, Z are -C (R ¹ ) = or N; R ¹ is hydrogen or C _1-3 alkyl and V is N or C (ie carbon And A is a bond or an alkylene linker having 1 to 3 capital reductions, provided that A is a bond, V must be CH, and R is ethyl, propyl, branched C _{3- 6} alkyl cyclic C _3-8 alkyl, m and n are 1 to 3, D is halogen, hydroxy, cyano, alkyl, cycloalkyl, alkoxy, — (CH ₂ ) _O — (C═O) _p -NR ² R ³ is optionally substituted heteroaryl, or D is hydrogen, halogen, hydroxy, cyano, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfinyl, heterocyclyl, heterocyclylalkyl , Telocyclylalkoxy, heterocyclylcarbonyl, alkylcarbonyl, alkoxycarbonyl, alkylcarboxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, arylcarbonylamino, arylcarbonylaminoalkyl, heteroarylcarbonylamino or heteroaryl Carbonylaminoalkyl, aryl (optionally substituted with one or more groups independently selected from — (CH ₂ ) _O — (C═O) _P —NR ² R ³ , and o is 0-3 And p is 0 or 1, and R ² and R ³ are independently hydrogen, alkyl or cycloalkyl; or R ² and R ³ together with the bound nitrogen form a heterocyclyl group Compound} And their salts and solvates have binding affinity for the histamine H3 receptor.

Description

  The present invention relates to novel compounds, uses of the compounds in pharmaceutical compositions, pharmaceutical compositions containing the compounds, and methods of treatment using these compounds or compositions. The compounds of the present invention exhibit high and selective binding affinity for the histamine H3 receptor and exhibit histamine H3 receptor antagonist, inverse agonist, or agonist activity. As a result, the compounds are useful for the treatment of diseases or disorders associated with histamine H3 receptors.

  The existence of the histamine H3 receptor has been known for several years, and such receptors are a current concern for the development of new medicines. Recently, the human histamine H3 receptor has been cloned. The histamine H3 receptor is a presynaptic autoreceptor located in both the central and peripheral nervous system, skin and tissues, such as the lung, intestine, possibly the spleen and digestive tract. Recent evidence suggests that the H3 receptor exhibits endogenous constitutive activity in vitro as well as in vivo (ie, active in the absence of agonist). Compounds that act as inverse agonists can suppress this activity. The histamine H3 receptor has been shown to modulate the release of histamine as well as other neurotransmitters such as serotonin and acetylcholine. A histamine H3 receptor antagonist or inverse agonist is expected to result in increased release of these neurotransmitters in the brain. A histamine H3 receptor agonist, conversely, leads to inhibition of histamine biosynthesis and also leads to inhibition of release of histamine and other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists, and antagonists can be important mediators of neural activity. The histamine H3 receptor is therefore an important target for new therapies.

  In view of the interest in the art for histamine H3 receptor agonists, inverse agonists, and antagonists, novel compounds that interact with the histamine H3 receptor would be a strongly desired contribution for the art. Several documents disclose the production and use of histamine H3 agonists and antagonists. While early H3 ligands were more or less approximate analogues of histamine, new imidazole-free ligands for the histamine 3 receptor have been described (eg, Linney et al. J. Med. Chem 2000, 43, US 6,316,475, WO 01/66534, WO 01/74810, and review of Celanire et al. In Drug Discov. Today 10: 16-1627).

  WO 00/66578 claims certain 3- or 4- (imidazol-2-yl) pyridines substituted at the 4-position of the imidazole ring. It is mentioned that mammals having a disease or condition mediated by NPY can be treated with such compounds.

  WO 2003/066604 (Applicant Internal Reference Number: 6447), a prior application by the present applicant, claims certain piperazines substituted at the 1st and 4th positions.

  WO 2005/009976 A1 (Applicant internal serial number: 6739), which is a prior application by the applicant, is a 3- (4-isopropylpiperazin-1-yl) -6-phenylpyridazine substituted at the para position of the phenyl ring. Claim a class. In the specification, no pharmacological data was given for the prepared compounds.

  WO 2005/028438 claims certain piperazines substituted at the 1- and 4-positions.

  The object of the present invention is to eliminate or reduce at least some of the disadvantages of the prior art. Thus, not all of the objects mentioned below may be completely eliminated or alleviated. Further objects of the invention are mentioned below.

Definitions In the structural formulas given herein, and throughout this specification, the following phrases have the meanings described:

The phrase “hydroxy” refers to the radical —OH, the phrase “oxy” refers to the radical “—O—”, the phrase “oxo” refers to the radical ═O, and the phrase “carbonyl”. Means the radical —C (═O) —, the phrase “sulfinyl” refers to the radical — (S═O) —, and the phrase “sulfonyl” refers to the radical —S (═O) ₂ —. The term “carboxy” means the radicals — (C═O) O— and —C (═O) OH, the term “amino” means the radical —NH ₂ and “nitro” The phrase means the radical —NO ₂ and the phrase “cyano” means the radical —CN.

The phrase “C _2-6 -alkenyl” refers to a branched or straight hydrocarbon group having 2 to 6 carbon atoms and at least one double bond, for example C _2-6 -alkenyl, C Represents _3-6 -alkenyl and the like. Representative examples are ethenyl (or vinyl), propenyl (eg, prop-1-enyl and prop-2-enyl), butadienyl (eg, buta-1,3-dienyl), butenyl (eg, buta-1- En-1-yl and but-2-en-1-yl), pentenyl (eg, penta-1-en-1-yl and penta-2-en-2-yl), hexenyl (eg, hexa-1- En-2-yl and hexa-2-en-1-yl), 1-ethylprop-2-enyl, 1,1- (dimethyl) prop-2-enyl, 1-ethylbut-3-enyl, 1,1- (Dimethyl) but-2-enyl and the like.

Similarly, the term “C _3-8 -alkenyl” as used herein refers to a branched or straight chain hydrocarbon group having from 3 to 8 carbon atoms and at least one double bond, such as C _3-6 -alkenyl and the like are represented. Representative examples are propenyl (eg, prop-1-enyl and prop-2-enyl), butadienyl (eg, but-1,3-dienyl), butenyl (eg, but-1-en-1-yl and But-2-en-1-yl), pentenyl (eg, penta-1-en-1-yl and penta-2-en-2-yl), hexenyl (eg, hexa-1-en-2-yl and Hex-2-en-1-yl), 1-ethylprop-2-enyl, 1,1- (dimethyl) prop-2-enyl, 1-ethylbut-3-enyl, 1,1- (dimethyl) but-2 -Enil.

As used herein, the phrase “C _1-6 -alkoxy” refers to the radical C _1-6 -alkyl-O—. Representative examples are methoxy, ethoxy, propoxy (eg, 1-propoxy and 2-propoxy), butoxy (eg, 1-butoxy, 2-butoxy and 2-methyl-2-propoxy), pentoxy (1-pentoxy and 2-penta-oxy), hexoxyhexoxy (1-hexoxy and 3-hexoxy) and the like.

As used herein, the term “C _1-6 -alkoxy-C _1-6 -alkyl” refers to C _1-6 -alkyl substituted at any carbon atom by C _1-6 -alkoxy. Representative examples are methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxyprop-1-yl and the like.

As used herein, “C _1-6 -alkoxycarbonyl” refers to the radical C _1-6 -alkoxy-C (═O) —. Representative examples are methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl, 2-propoxycarbonyl, 1-butoxycarbonyl, 2-butoxycarbonyl, 2-methyl-2-propoxycarbonyl, 3-methylbutoxycarbonyl, 1-hex. And so on.

As used herein, the phrase “C _1-6 -alkyl” refers to a saturated, branched, or straight chain hydrocarbon group having 1 to 6 carbon atoms, eg, C _1-3 -alkyl. , C _1-4 -alkyl, C _2-6 -alkyl, C _3-6 -alkyl and the like. Representative examples are methyl, ethyl, propyl (eg, prop-1-yl and prop-2-yl (or isopropyl)), butyl (eg, 2-methylprop-2-yl (or tert-butyl), butane -1-yl and but-2-yl), pentyl (eg, penta-1-yl, penta-2-yl and penta-3-yl), 2-methylbut-1-yl, 3-methylbut-1-yl Hexyl (eg, hexa-1-yl), heptyl (eg, hept-1-yl), and the like.

Similarly, the term “C _1-8 -alkyl” as used herein refers to a saturated, branched, or straight chain hydrocarbon group having 1 to 8 carbons, such as C _1-3. -Alkyl, C _1-4 -alkyl, C _1-6 -alkyl, C _2-6 -alkyl, C _3-6 -alkyl, C _1-8 -alkyl, etc. Representative examples are methyl, ethyl, propyl (eg, prop-1-yl and prop-2-yl (or isopropyl)), butyl (eg, 2-methylprop-2-yl (or tert-butyl), butane -1-yl and but-2-yl), pentyl (eg, penta-1-yl, penta-2-yl and penta-3-yl), 2-methylbut-1-yl, 3-methylbut-1-yl Hexyl (eg, hexa-1-yl), heptyl (eg, hept-1-yl), octyl (eg, octa-1-yl), and the like.

As used herein, the phrase “C _1-6 -alkylcarbonyl” refers to the radical C _1-6 -alkyl-C (═O) —. Representative examples are acetyl (eg, methylcarbonyl), propionyl (eg, ethylcarbonyl), butanoyl (eg, prop-1-ylcarbonyl and prop-2-ylcarbonyl), and the like.

“C _1-6 -alkylcarbonylamino” as used herein refers to the radical C _1-6 -alkyl-C (═O) —NH—. Representative examples are acetylamino, propionylamino, pivaloylamino, valeroylamino, and the like.

"C _1-6 alkylcarbonylamino -C _1-6 - alkyl" as used herein the phrase is, at any carbon atom, C _1-6 substituted by C _1-6 alkylcarbonylamino - alkyl Point to. Representative examples are acetylaminomethyl, 1- (acetylamino) ethyl, propionylaminomethyl, and the like.

As used herein, the phrase “C _1-6 alkylcarboxy” refers to the radical C _1-6 -alkyl-C (═O) O—. Representative examples refer to methylcarboxy, ethylcarboxy, propylcarboxy (eg, prop-1-yl-carboxy, prop-2-ylcarboxy) and the like.

As used herein, the phrase “C _1-6 -alkylsulfanyl” refers to the radical C _1-6 -alkyl-S—. Representative examples refer to methylthio, ethylthio, propylthio (eg, 1-propylthio, 2-propylthio and 3-propylthio), butylthio, pentylthio, hexylthio and the like.

“C _1-6 -alkylsulfinyl” as used herein refers to the radical C _1-6 -alkyl-S (═O) —. Representative examples refer to methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentyl-sulfinyl, hexylsulfinyl and the like.

As used herein, the phrase “C _1-6 -alkylsulfonyl” refers to the radical C _1-6 -alkyl-S (═O) ₂ —. Representative examples refer to methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, and the like.

As used herein, the term “C _3-8 -alkynyl” represents a branched or straight chain hydrocarbon group having 3 to 8 carbon atoms and at least one triple bond. Representative examples are propynyl (eg, prop-1-ynyl and prop-2-ynyl), butynyl (eg, but-1-ynyl and but-2-ynyl), pentynyl (eg, penta-1-ynyl and Penta-2-ynyl), hexynyl (eg, hexa-1-ynyl and hexa-2-ynyl), 1-ethylprop-2-ynyl, 1,1- (dimethyl) prop-2-ynyl, 1-ethylbuta-3 -Inyl, 1,1- (dimethyl) but-2-ynyl and the like.

  As used herein, the term “aryl” is intended to include monocyclic, bicyclic, or polycyclic carbocyclic aromatic rings. Representative examples are phenyl, naphthyl (eg, naphth-1-yl and naphth-2-yl), anthryl (eg, anthra-1-yl and anthra-9-yl), phenanthryl (eg, phenanthra-1- Phenanthr-1-yl and phenanthr-9-yl. Aryl is intended to include monocyclic, bicyclic, or polycyclic carbocyclic aromatic rings substituted with carbocyclic aromatic rings. Representative examples are biphenyl (eg, biphenyl-2-yl, biphenyl-3-yl and biphenyl-4-yl), phenylnaphthyl (eg, 1-phenylnaphth-2-yl and 2-phenylnaphth-1-yl). Il). Aryl is intended to include saturated bicyclic or polycyclic carbocycles having moieties having at least one unsaturated moiety (eg, a benzo moiety). Representative examples are indanyl (eg, indan-1-yl, indan-5-yl), indenyl (eg, inden-1-yl and inden-5-yl), 1,2,3,4-tetrahydronaphthyl. (Eg, 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl and 1,2,3,4-tetrahydro-naphth-6-yl), 1,2-dihydronaphthyl (eg 1,2-dihydronaphth-1-yl, 1,2-dihydronaphth-4-yl and 1,2-dihydronaphth-6-yl), fluorenyl (eg fluorene-1 -Yl, fluoren-4-yl and fluoren-9-yl). Aryl is intended to include partially saturated bicyclic or polycyclic carboaromatic rings containing one or two bridges. Representative examples are benzonorbornyl (eg, benzonorborn-3-yl and benzonorborn-6-yl), 1,4-ethanoethano-1,2,3 , 4-tetrahydronaphthyl (eg 1,4-ethano-1,2,3,4-tetrahydronaphth-2-yl and 1,4-ethano-1,2,3,4-tetrahydronaphth-10-yl) Etc. Aryl is intended to include partially saturated bicyclic or polycyclic carboaromatic rings containing one or more spiro atoms. Representative examples are spiro [cyclo-pentane-1,1′-indane] -4-yl, spiro [cyclopentane-1,1′-indene] -4-yl, spiro [piperidine-4,1′-yl. Indan] -1-yl, spiro [piperidine-3,2′-indan] -1-yl, spiro [piperidine-4,2′-indan] -1-yl, spiro [piperidine-4,1′-indan] -3'-yl, spiro [pyrrolidin-3,2'-indan] -1-yl, spiro [pyrrolidin-3,1 '-(3', 4'-dihydro-naphthalene)]-1-yl, spiro [ Piperidin-3,1 ′-(3 ′, 4′-dihydronaphthalene)]-1-yl, spiro [piperidin-4,1 ′-(3 ′, 4′-dihydronaphthalene)]-1-yl, spiro [ Imidazolidin-4,2′-indan] -1-yl, spiro [piperidin-4,1′-indene] -1-yl, and the like.

As used herein, the phrase “aryl-C _1-6 -alkoxycarbonyl” refers to the radical aryl-C _1-6 -alkoxy-C (═O) —. Representative examples are benzyloxycarbonyl, phenylethoxycarbonyl (eg, (2-phenylethoxy) carbonyl and (1-phenylethoxy) carbonyl), and the like.

  As used herein, the phrase “arylcarbonyl” refers to the radical aryl-C (═O) —. Representative examples are benzoyl, naphthylcarbonyl, 4-phenylbenzoyl, anthrylcarbonyl, phenanthryl-carbonyl, and the like.

  As used herein, the term “arylcarbonylamino” refers to the radical aryl-C (═O) —. Representative examples refer to benzoylamino, naphthylcarbonylamino, 4-phenylbenzoylamino, and the like.

As used herein, the phrase “arylcarbonylamino-C _1-6 -alkyl” refers to C _1-6 -alkyl substituted at any carbon atom with an arylcarbonylamino. Representative examples are benzoylaminomethyl, naphthylcarbonylaminomethyl, 2- (4-phenylbenzoylamino) ethyl, and the like.

As used herein, the phrase “arylsulfonyl” refers to the radical aryl-S (═O) ₂ —. Representative examples are phenylsulfonyl, (4-methylphenyl) sulfonyl, (4-chlorophenyl) sulfonyl, naphthyl-sulfonyl and the like.

The phrase “cyano-C _1-6 alkyl” as used herein refers to C _1-6 alkyl substituted at any carbon with cyano. Representative examples are cyanomethyl, 2-cyanoethyl and the like.

The term “C _3-8 -cycloalkenyl” as used herein represents a partially saturated monocyclic carbocycle having 3 to 8 carbon atoms and at least one double bond. Representative examples are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexa-1,3-dienyl and the like.

Clearly, “C _3-8 -cycloalkenyl-C _1-3 -alkyl” is a combination of C _{3-8 -cyclo} -alkenyl and C _1-3 -alkyl. Representative examples are cyclopenten-1-ylmethyl, 3- (cyclohexen-1-yl) propyl, and the like.

The term “C _3-8 -cycloalkyl” as used herein represents a saturated monocyclic carbocycle having from 3 to 8 carbon atoms, such as C _3-6 -alkyl and the like. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. C _3-8 -cycloalkyl is a saturated bicyclic carbocycle having from 4 to 8 carbon atoms. Representative examples are decahydronaphthalenyl, bicyclic- [3.3.0] octanyl, and the like. C _3-8 -cycloalkyl is intended to represent a saturated carbocyclic ring having 3 to 8 carbon atoms and containing 1 or 2 carbon bridges. Representative examples are adamantyl, norbornanyl, nortricyclyl, bicyclo [3.2.1] octanyl, bicyclo- [2.2.2] octanyl, tricyclo [5.2.1.0/2,6]. Decanyl, bicyclo [2.2.1] heptyl and the like. C _3-8 -cycloalkyl is intended to represent a saturated carbocyclic ring having from 3 to 8 carbon atoms and having one or more spiro atoms. Representative examples are spiro [2.5] octanyl, spiro- [4.5] decanyl and the like.

Clearly, the phrase “C _3-8 -cycloalkyl-C _1-3 -alkyl” is a combination of C _3-8 -cycloalkyl and C _1-3 -alkyl. Representative examples are cyclopropylmethyl, 2-cyclohexylethyl, 3-cyclopentyl-prop-1-yl, 1-cyclohexylethyl, adamantylmethyl and the like.

Representative examples of “C _3-8 -cycloalkylcarbonylamino-C _1-6 -alkyl” as used herein include cyclopentylcarbonylaminomethyl, 3- (cyclohexylcarbonylamino) propyl, and the like.

As used herein, the phrase “halo-C _1-6 -alkyl” refers to C _1-6 -alkyl substituted at any carbon atom with any halogen. Representative examples are trifluoromethyl, 2,2,2-trifluoroethyl and the like.

As used herein, “halo-C _1-6 -alkoxy” refers to C _1-6 -alkoxy substituted at any carbon atom one or more times with any halogen. Representative examples include trifluoro-methoxy and 2,2,2-trifluoroethoxy.

The phrase “halogen” or “halo” means fluorine, chlorine, bromine or iodine. As used herein, the term “heteroaryl” is intended to include monocyclic heteroaromatic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, SO and S (═O) _2. To do. Representative examples are pyrrolyl (eg, pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl), furanyl (eg, furan-2-yl and furan-3-yl), thienyl (eg, Thien-2-yl and thien-3-yl), oxazolyl (eg oxazol-2-yl, oxazol-4-yl and oxazol-5-yl), thiazolyl (eg thiazol-2-yl, thiazol-4-yl) Yl and thiazol-5-yl), imidazolyl (eg imidazol-2-yl, imidazol-4-yl and imidazol-5-yl), pyrazolyl (eg pyrazol-1-yl, pyrazol-3-yl and pyrazole- 5-yl), isoxazolyl (eg, isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl), isothiazolyl (eg, isothiazol-3-yl) Isothiazol-4-yl and isothiazol-5-yl), 1,2,3-triazolyl (eg 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl and 1 , 2,3-Triazol-5-yl), 1,2,4-triazolyl (eg, 1,2,4-triazol-yl, 1,2,4-triazol-3-yl and 1,2,4- Triazol-5-yl), 1,2,3-oxadiazolyl (eg 1,2,3-oxadiazol-4-yl and 1,2,3-oxadiazol-5-yl), 1,2, 4-oxadiazolyl (eg, 1,2,4-oxadiazol-3-yl and 1,2,4-oxadiazol-5-yl), 1,2,5-oxadiazolyl (eg, 1,2,5 -Oxadiazol-3-yl and 1,2,5-oxadiazol-4-yl), 1,3,4-oxadiazolyl (eg 1,3,4-oxadiazol-2-yl and 1, 3, -Oxadiazol-5-yl), 1,2,3-thiadiazolyl (eg, 1,2,3-thiadiazolyl-4-yl and 1,2,3-thiadiazolyl-5-yl), 1,2,4 -Thiadiazolyl (eg 1,2,4-thiadiazolyl-3-yl and 1,2,4-thiadiazolyl-5-yl), 1,2,5-thiadiazolyl (eg 1,2,5-thiadiazolyl-3-yl) Yl and 1,2,5-thiadiazolyl-4-yl), 1,3,4-thiadiazolyl (eg, 1,3,4-thiadiazolyl-2-yl and 1,3,4-thiadiazolyl-5-yl), Tetrazolyl (eg, tetrazol-1-yl and tetrazol-5-yl), pyranyl (eg, pyran-2-yl), pyridinyl (eg, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl) Pyridazinyl (eg, pyridazin-2-yl and pyridazin-3-yl), pyrimidinyl (eg, Pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl), pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, thiadiazinyl, azepinyl, azesinyl It is. Heteroaryl is intended to include bicyclic heteroaromatic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S (═O) and S (═O) ₂ . Representative examples are indolyl (eg, indol-1-yl, indol-2-yl, indol-3-yl and indol-5-yl), isoindolyl, benzofuranyl (eg, benzo [b] furan-2-yl Benzo [b] furan-3-yl, benzo- [b] furan-5-yl, benzo [c] furan-2-yl, benzo [c] furan-3-yl and benzo [c] furan-5- Yl), benzothienyl (eg, benzo [b] thien-2-yl, benzo [b] thien-3-yl, benzo [b] thien-5-yl, benzo [c] thien-2-yl, benzo [ c] -thien-3-yl and benzo [c] thien-5-yl), indazolyl (eg, indazol-1-yl, indazol-3-yl and indazol-5-yl), indolizinyl (eg, indolizinyl- 1-yl and indolizine-3-yl), Zopyranyl (eg, benzo [b] pyran-3-yl, benzo [b] pyran-6-yl, benzo [c] pyran-1-yl and benzo [c] pyran-7-yl), benzimidazolyl (eg, Benzimidazol-1-yl, benzimidazol-2-yl and benzimidazol-5-yl), benzothiazolyl (eg benzothiazol-2-yl and benzothiazol-5-yl), benzisothiazolyl, benzoxazolyl , Benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl (eg, 1,8-naphthyridin-2-yl, 1,7-naphthyridin-2-yl and 1,6-naphthyridin-2-yl), phthalazinyl (Eg, phthalazin-1-yl and phthalazin-5-yl), pteridinyl, purinyl (eg, purin-2-yl, purin-6-yl, purin-7-y , Purin-8-yl and purin-9-yl), quinazolinyl (eg, quinazolin-2-yl, quinazolin-4-yl and quinazolin-6-yl), cinnolinyl, quinolinyl (eg, quinolin-2-yl, quinoline) -3-yl, quinolin-4-yl and quinolin-6-yl), isoquinolinyl (eg isoquinolin-1-yl, isoquinolin-3-yl and isoquinolin-4-yl), quinoxalinyl (eg quinoxalin-2-yl) And quinoxalin-5-yl), pyrrolopyridinyl (eg, pyrrolo [2,3-b] pyridinyl, pyrrolo [2,3-c] pyridinyl and pyrrolo [3,2-c] pyridinyl), furopyridinyl (eg, furo [2 , 3-b] pyridinyl, furo [2,3-c] pyridinyl and furo [3,2-c] pyridinyl), thienopyridinyl (eg, thieno- [2,3-b] pyridinyl, thieno [2 , 3-c] pyridinyl and thieno [3,2-c] pyridinyl), imidazopyridinyl (eg, imidazo [4,5-b] pyridinyl, imidazo [4,5-c] pyridinyl, imidazo [1,5 -a] pyridinyl and imidazo [1,2-a] -pyridinyl), imidazopyrimidinyl (eg imidazo [1,2-a] pyrimidinyl and imidazo [3,4-a] pyrimidinyl), pyrazolopyridinyl (eg , Pyrazolo [3,4-b] pyridinyl, pyrazolo [3,4-c] pyridinyl and pyrazolo [1,5-a] -pyridinyl), pyrazolopyrimidinyl (eg pyrazolo [1,5-a] pyrimidinyl and pyrazolo [3,4-d] pyrimidinyl), thiazolopyridinyl (eg thiazolo [3,2-d] pyridinyl), thiazolopyrimidinyl (eg thiazolo [5,4-d] -pyrimidinyl), imidazothiazo Le (e.g., imidazo [2,1-b] thiazolyl), triazolopyridinyl pyridinylcarbonyl (e.g., triazolo - [4,5-b] pyridinyl), triazolopyrimidinyl (e.g., 8-Azapuriniru) and the like. Heteroaryl is intended to include polycyclic heteroaromatic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S (═O) and S (═O) ₂ . Representative examples are carbazolyl (eg, carbazol-2-yl, carbazol-3-yl, carbazol-9-yl), phenoxazinyl (eg, phenoxazin-10-yl), phenazinyl (eg, phenazin-5-yl). ), Acridinyl (eg, acridine-9-yl and acridine-10-yl), phenol-thiazinyl (eg, phenothiazin-10-yl), carbolinyl (eg, pyrido [3,4-b] indol-1-yl, Pyrido [3,4-b] indol-3-yl), phenanthrolinyl (eg, phenanthroline-5-yl) and the like. Heteroaryl is intended to refer to one or more heteroatoms partially saturated monocyclic, bicyclic or polycyclic heterocycles selected from nitrogen, oxygen, sulfur, S (═O) and S (═O) ₂ To do. Representative examples are pyrrolinyl, pyrazolinyl, imidazolinyl (eg, 4,5-dihydroimidazol-2-yl and 4,5-dihydroimidazol-1-yl), indolinyl (eg, 2,3-dihydroindol-1-yl). And 2,3-dihydroindol-5-yl), dihydro-benzofuranyl (eg, 2,3-dihydrobenzo [b] furan-2-yl and 2,3-dihydrobenzo [b] furan-4-yl), Dihydro-benzothienyl (eg 2,3-dihydrobenzo [b] thien-2-yl and 2,3-dihydrobenzo [b] thien-5-yl), 4,5,6,7-tetrahydrobenzo [b ] Furan-5-yl), dihydrobenzopyranyl (eg 3,4-dihydrobenzo [b] pyran-3-yl, 3,4-dihydrobenzo [b] pyran-6-yl, 3,4-dihydro Benzo [c] pyran-1-yl and dihydro Nzo [c] pyran-7-yl), oxazolinyl (eg, 4,5-dihydrooxazol-2-yl, 4,5-dihydrooxazol-4-yl and 4,5-dihydrooxazol-5-yl), Isoxazolinyl, oxazepinyl, 2,4-dioxodihydropyrimidin-3-yl, tetrahydroindazolyl (eg, 4,5,6,7-tetrahydroindazol-1-yl, 4,5,6,7-tetrahydroindazole- 3-yl, 4,5,6,7-tetrahydroindazol-4-yl and 4,5,6,7-tetrahydroindazol-6-yl), tetrahydrobenzimidazolyl (eg, 4,5,6,7-tetrahydro) Benz-imidazol-1-yl and 4,5,6,7-tetrahydrobenzimidazol-5-yl), tetrahydroimidazo [4,5-c] pyridyl (eg, 4,5,6,7-tetrahydroimidazo [ , 5-c] pyrida-1-yl, 4,5,6,7-tetrahydroimidazo [4,5-c] pyrida-5-yl and 4,5,6,7-tetrahydroimidazo [4,5-c ] Pyrida-6-yl), tetrahydroquinolinyl (eg 1,2,3,4-tetrahydro-quinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrahydroisoquinolinyl (eg 1 , 2,3,4-tetrahydro-isoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinoxalinyl (eg 1,2,3,4-tetra-hydroquinoxalinyl and 5 , 6,7,8-tetrahydroquinoxalinyl), 2,3-dihydrobenzo [1,4] dioxin-6-yl, 2,3-dihydrobenzo [1,4] dioxin-5-yl, 2, 3-Dihydrobenzo [1,4] dioxin-2-yl, benzo [1,3] dioxol-4-yl, benzo- [1,3 Dioxol-5-yl, benzo [1,3] dioxol-2-yl, 3,4-dihydro-2H-benzo [1,4] oxazin-7-yl, 4-methyl-3,4-di-hydro- 2H-benzo [1,4] oxazin-7-yl and the like. Heteroaryl is intended to include partially saturated bicyclic or polycyclic heterocycles containing one or more spiro atoms. Representative examples are spiro [isoquinoline-3,1′-cyclohexane] -1-yl, spiro [piperidin-4,1′-benzo- [c] thiophene] -1-yl, spiro [piperidine-4,1 '-Benzo [c] furan] -1-yl, spiro [piperidin-4,3'-benzo [b] -furan] -1-yl, spiro [piperidin-4,3'-coumarin] -1-yl, etc. It is.

  As used herein, the phrase “heteroarylcarbonyl” is the radical heteroaryl-C (═O) —. Representative examples are pyridinylcarbonyl (eg, pyridin-2-ylcarbonyl and pyridin-4-ylcarbonyl), quinolinylcarbonyl (eg, 2- (quinolin-2-yl) carbonyl and 1- (quinoline). -2-yl) carbonyl), imidazolylcarbonyl (eg, imidazol-2-ylcarbonyl and imidazol-5-ylcarbonyl) and the like.

  As used herein, the term “heteroarylcarbonylamino” refers to the radical heteroaryl-C (═O) —NH—. Representative examples are pyridinylcarbonylamino (eg, pyridin-2-ylcarbonyl-amino and pyridin-4-ylcarbonylamino), quinolinylcarbonylamino (eg, 2- (quinolin-2-yl)- Carbonylamino and 1- (quinolin-2-yl) carbonylamino) and the like.

As used herein, the phrase “heteroarylcarbonylamino-C _1-6 -alkyl” refers to C _1-6 -alkyl substituted at any carbon atom with a heteroarylcarbonylamino. Representative examples are pyridinylcarbonylaminomethyl (eg, pyridin-2-ylcarbonylaminomethyl and pyridin-4-yl-carbonylaminomethyl), 2- (quinolinylcarbonylamino) ethyl (eg, 2- (2- (quinolin-2-yl) carbonyl-amino) ethyl and 2- (1- (quinolin-2-yl) carbonylamino) ethyl) and the like.

As used herein, the phrase “heterocyclyl” is a 3-8 membered containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S (═O), and S═ (O) ₂ . Represents a saturated monocycle. Representative examples are aziridinyl (eg, aziridin-1-yl), azetidinyl (eg, azetidin-1-yl and azetidin-3-yl), oxetanyl, pyrrolidinyl (eg, pyrrolidin-1-yl, pyrrolidin-2-yl). Yl and pyrrolidin-3-yl), 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, imidazolidinyl (eg imidazolidin-1-yl, imidazolidin-2-yl and imidazolidine) -4-yl), 2,4-dioxo-imidazolidin-3-yl, 2,4-dioxo-1-methylimidazolidin-3-yl, 2,4-dioxo-1,5,5-trimethylimidazolidine -3-yl, 2,4-dioxo-5,5-dimethyl-imidazolidin-3-yl, oxazolidinyl (eg, oxazolidin-2-yl, oxazolidine-3-yl and oxazolidine-4-yl), 2-oxo - Oxazolidin-3-yl, thiazolidinyl (eg, thiazolidin-2-yl, thiazolidin-3-yl and thiazolidin-4-yl), 2,4-dioxo-thiazolidin-3-yl, isothiazolidinyl, 1,1- Dioxo-isothiazolidine-2-yl, 1,1-dioxo- [1,2,5] thia-diazolidine-2-yl, piperidinyl (eg piperidin-1-yl, piperidin-2-yl, piperidin-3- Yl and piperidin-4-yl), 2-oxopiperidin-1-yl, 2,6-dioxopiperidin-1-yl, homopiperidinyl (eg homopiperidin-1-yl, homo-piperidin-2-yl, homo Piperidin-3-yl and homopiperidin-4-yl), piperazinyl (eg piperazin-1-yl and piperazin-2-yl), morpholinyl (eg morpholin-2-yl, morpholin-3-yl and morpholin-3-yl) Rupholin-4-yl), 2-oxo- [1,3] oxazinan-3-yl, thiomorpholinyl (eg, thiomorpholin-2-yl, thiomorpholin-3-yl and thio-morpholin-4-yl), 1 -Oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, tetrahydrofuranyl (eg, tetrahydrofuran-2-yl and tetrahydrofuran-3-yl), tetrahydrothienyl, tetrahydro-1,1-dioxothienyl, tetrahydropyranyl (eg, 2-tetrahydropyranyl), tetrahydrothiopyranyl (eg 2-tetrahydrothio-pyranyl), 1,4-dioxanyl, 1,3-dioxanyl and the like. Heterocycle is intended to represent a saturated 6-12 membered bicycle containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S (= O) and S (= O) ₂ . Representative examples are octahydroindolyl (eg, octahydroindol-1-yl, octahydroindol-2-yl, octahydroindol-3-yl and octahydroindol-5-yl), decahydroquinolinyl (Eg, decahydroquinolin-1-yl, decahydroquinolin-2-yl, decahydroquinolin-3-yl, decahydrodecahydroquinolin-4-yl and decahydroquinolin-6-yl), decahydroquinoxali Nil (eg, decahydroquinoxalin-1-yl, decahydroquinoxalin-2-yl and decahydroquinoxalin-6-yl) and the like. Heterocycle represents a saturated 6-12 membered ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S (═O) and S (═O) ₂ and containing one or two bridges. . Representative examples are 3-azabicyclo [3.2.2] nonyl, 2-azabicyclo- [2.2.1] heptyl, 3-azabicyclo [3.1.0] hexyl, 2,5-diazabicyclo [2 2.2.1] heptyl, atropinyl, tropinyl, quinuclidinyl, 1,4-diazabicyclo [2.2.2] octanyl and the like. The heterocycle contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, S (= O) and S (= O) ₂ , and a 6-12 membered saturated ring containing one or more spiro atoms. Is intended to represent Representative examples are 1,4-dioxaspiro [4.5] decanyl (eg, 1,4-dioxaspiro [4.5] decan-2-yl and 1,4-dioxaspiro [4.5] decane-7- Yl), 1,4-dioxa-8-azaspiro [4.5] decanyl (eg, 1,4-dioxa-8-azaspiro- [4.5] decan-2-yl and 1,4-dioxa-8- Azaspiro [4.5] decan-8-yl), 8-azaspiro [4.5] decanyl (eg, 8-aza-spiro [4.5] decan-1-yl and 8-azaspiro [4.5] decane -8-yl), 2-azaspiro [5.5] undecanyl (eg 2-aza-spiro [5.5] undecan-2-yl), 2,8-diazaspiro [4.5] decanyl (eg 2 , 8-diazaspiro [4.5] decan-2-yl and 2,8-diazaspiro [4.5] decan-8-yl), 2,8-diazaspiro [5.5] undeca (Eg, 2,8-diazaspiro [5.5] un-decan-2-yl), 1,3,8-triazaspiro [4.5] decanyl (eg, 1,3,8-triazaspiro [4.5 Decan-1-yl and 1,3,8-triazaspiro [4.5] decan-3-yl, 1,3,8-triazaspiro [4.5] decan-8-yl).

As used herein, the phrase “heterocyclyl-C _1-6 -alkoxy” refers to the radical heterocyclyl-C _1-6 -alkoxy. Representative examples are piperidin-1-ylmethoxy, 2- (piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) prop-3-oxy, piperazin-1-ylmethoxy, 2- (piperazine-1 -Yl) ethoxy, 3- (piperazin-1-yl) -prop-3-oxy, morpholin-4-ylmethoxy, 2- (morpholin-4-yl) ethoxy, 3- (morpholin-4-yl) propa-3 -Oxy and so on.

As used herein, the phrase “heterocyclyl-C _1-6 -alkyl” refers to the radical heterocyclyl-C _1-6 -alkyl. Representative examples are piperidin-1-ylmethyl, 2- (piperidin-1-yl) ethyl, 3-hydroxy-3- (piperidin-1-yl) propyl, piperazin-1-ylmethyl, 2- (piperazine-1 -Yl) ethyl, 3-hydroxy-3- (piperazin-i-yl) propyl, morpholin-4-ylmethyl, 2- (morpholin-4-yl) ethyl, 3-hydroxy-3- (morpholin-4-yl) Such as propyl.

  “Heterocyclylcarbonyl” as used herein refers to the radical heterocyclyl-C (═O) —. Representative examples include piperidinylcarbonyl (eg, piperidin-2-ylcarbonyl, piperidin-3-ylcarbonyl and piperidin-4-ylcarbonyl), piperazinylcarbonyl (eg, piperazin-1-yl-carbonyl and Piperazin-2-ylcarbonyl) and the like.

As used herein, the term “hydroxy-C _1-6 -alkyl” refers to C _1-6 -alkyl substituted one or more times with hydroxyl at any carbon atom. Representative examples are hydroxymethyl, hydroxyethyl (eg, 1-hydroxyethyl and 2-hydroxyethyl), and the like.

As used herein, the phrase “N— (C _1-6 -alkylcarbonyl) -N— (C _1-6 -alkyl) amino” refers to two substituents, namely C _1-6 -alkylcarbonyl. And an amino group having a C _1-6 -alkyl group. Similarly, the following phrases N- (C _3-8 -cycloalkylcarbonyl) -N- (C _1-6 -alkyl) amino and N- (C _3-8 -cycloalkyl-C _1-6 -alkylcarbonyl) -N- (C _1-6 -alkyl) amino covers groups in which the amino group has two substituents. Similarly, the following phrases: N- (C _1-6 -alkylcarbonyl) -N- (C _1-6 -alkyl) -amino-C _1-6 -alkyl, N- (C _3-8 -cycloalkylcarbonyl ) -N- (C _1-6 -alkyl) amino-C _1-6 -alkyl and N- (C _{3-8 -cyclo} -alkyl-C _1-6 -alkylcarbonyl) -N- (C _1-6- Alkyl) amino-C _1-6 -alkyl covers groups in which two substituents are present on the nitrogen in the amino-C _1-6 -alkyl moiety. Representative examples are N-cyclo-hexylcarbonyl-N-methylamino, 2- (N-cyclopentylcarbonyl-N-methylamino) ethyl and the like.

As used herein, the phrase “bridged” is a linkage in a saturated or partially saturated ring, and carbon, nitrogen, oxygen and sulfur between two atoms not adjacent to such a ring. Means a connection through a chain of 1 to 4 atoms selected from Examples of such coupling _{chains, -CH 2 -, - CH 2} CH 2 -, - CH 2 NHCH 2 -, - CH 2 CH 2 CH 2 -, - CH 2 OCH 2 - and the like.

As used herein, the phrase “spiro atom” refers to a carbon atom in a saturated or partially saturated ring that connects both ends of a chain of 3-8 atoms selected from carbon, nitrogen, oxygen, and sulfur. Represents. Representative examples _{are, - (CH 2) 5 -} , - (CH 2) 3 -, - (CH 2) 4 -, - CH 2 NHCH 2 CH 2 -, - CH 2 CH 2 NHCH 2 CH 2 -, —CH ₂ NHCH ₂ CH ₂ CH ₂ —, —CH ₂ CH ₂ OCH ₂ —, —OCH ₂ CH ₂ O— and the like.

  As used herein, “optionally substituted” means a group in which the group in question is unsaturated or substituted with one or more specific substituents. When the group in question is substituted with two or more substituents, the substituents may be the same or different.

A phrase among the defined phrases can occur more than once in the structural formula, and in such cases, each phrase is defined independently of the other phrases.
Certain of the defined phrases can occur in combination, and the first-mentioned radical is a substituent on the next-mentioned radical, to the substitution point, i.e. to the rest of the molecule. The point of attachment is on the radical mentioned at the end of the radical.

  As used herein, the phrase “solvate” is a complex of a given stoichiometry formed by a solute (ie, a compound described in the present invention) and a solvent. Solvates are solvents commonly used in the pharmaceutical field, such as water, ethanol, acetic acid and the like. The phrase “hydrate” refers to the complex where the solvent molecule is water.

  As used herein, the phrase “treatment” refers to the management and treatment of a patient intended to combat a disease, disorder, or condition. The phrase is intended to include delaying the progression of a disease, disorder, or condition, reducing or alleviating symptoms and complications, and / or curing or eliminating a disease, disorder, or condition. The patient to be treated is preferably a mammal, in particular a human.

  As used herein, the terms “disease”, “condition”, and “disorder” are used interchangeably to identify a patient's condition that is not a normal physiological condition in humans.

  As used herein, the phrase “medicament” means a pharmaceutical composition suitable for administration of a pharmaceutically active compound to a patient.

  As used herein, the phrase “prodrug” includes a biohydrolyzable amide and a biohydrolyzable ester, and (a) the biohydrolyzable functional group in such a prodrug has A compound contained in the compound described in the present invention and (b) a compound that can be biologically oxidized or reduced at a predetermined functional group are produced to produce the drug substance described in the present invention. Examples of these functional groups include 1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl and the like.

As used herein, the phrase “biohydrolyzable ester” refers to (a) a substance that does not interfere with the biological activity of the substance of the present invention, but has advantageous properties in vivo for the duration of action, onset of action, etc. Or (b) an ester of a drug substance (compound of formula I in the present invention) that is biologically inactive but is easily converted in vivo by the subject into a biologically active major component. is there. An advantage of this is, for example, that the biohydrolyzable ester is orally absorbed from the intestine and converted to (I) in plasma. Many such examples are known in the art and include, by way of example, alkyl esters (eg C _1-4 ), lower acyloxyalkyl esters, lower alkoxycyclooxyalkyl esters, alkoxyacyloxyesters, alkylacylaminoalkyls. Examples include esters and choline esters.

  As used herein, the phrase “biohydrolyzable amide” refers to (a) a substance that does not interact with the substance biological activity of the present invention, but has advantageous properties in vivo regarding duration of action, onset of action, etc. Or (b) a drug substance that is biologically inactive, but is easily converted in vivo by a subject into a biologically active main component (compound of general formula I in the present invention) Is an amide. An advantage of this is, for example, that biohydrolyzable amides are apt to be absorbed from the gut and converted to (I) in plasma. Many examples of such are known in the art and examples include lower alkyl amides, alpha amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

  As used herein, the phrase “pharmaceutically acceptable” means that it is suitable for normal pharmaceutical application, that is, does not cause an adverse event in a patient or the like.

  As used herein, the phrase “effective amount” means a dose that is sufficient to be effective for the treatment of the patient as compared to untreated.

  As used herein, the phrase “therapeutically effective amount” of a compound means an amount sufficient to ameliorate, alleviate, or partially stop the clinical symptoms of a given disease and its complications. An amount adequate to accomplish this is defined as a “therapeutically effective amount”. The effective amount for each purpose depends on the severity of the disease or injury as well as the weight and general state of the subject. It will be appreciated that the determination of an appropriate dose can be accomplished using routine experimentation by creating a numerical matrix and testing different points of the matrix. All of these are within the ordinary skill of a skilled physician or veterinarian.

  As used herein, the phrase “metabolite” is any intermediate or product produced by metabolism.

  As used herein, the term “metabolism” refers to the biotransformation of a drug substance (in the present invention, a compound of general formula I) that is administered to a patient.

  The representative examples mentioned above are specific embodiments of the present invention.

In the examples below, the following terms are intended to have the following general meaning: d is the day, g is the gram, h is the hour, Hz is the hertz, kD is the kilodalton, L is the liter, M is the Mol, mbar is millibar, mg is milligram, min is minute, ml is milliliter, mM is millimolar, mmol is mmol, mol is mol, N is usually parts per million, psi is pounds per square inch, APCI Is atmospheric pressure chemical ionization, ESI is electrospray ionization, Iv is intravenous administration, m / z is mass / charge ratio, mp / Mp is melting point, MS is mass spectrometry, HPLC is high pressure liquid chromatography, RP reverse phase, HPLC-MS is high pressure liquid chromatography mass spectrum, NMR each magnetic resonance spectroscopy, p.o.. oral administration, R _f is the relative TLC mobility, r . At room temperature, s.c subcutaneous administration, TLC is thin layer chromatography, t _r is the retention time, BOP is (1-benzotriazolyl-oxy) tris (dimethylamino) phosphonium hexafluorophosphate, CDI carbonyl - di Imidazole, DCM is dichloromethane, CH ₂ Cl ₂ is methylene chloride, DIBAL-H is diisobutyl-aluminum hydride, DBU is 1,8-diazabicyclo [5.4.0] undec-7-ene, DEAD is diethylazodicarboxy Rate, DIC is 1,3-diisopropylcarbodiimide, DIPEA is N, N-diisopropylethylamine, DMA is N, N-dimethylacetamide, DMF is N, N-dimethylformamide, DMPU is N, N-dimethylpropylene-urea, 1 , 3-Dimethyl-2-oxohexahydropyrimidine, DMSO Rusuruhokishido, EDAC is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, Et ₂ O diethyl ether, EtOAc is ethyl acetate, HMPA is hexamethyl phosphoric triamide, HOAt is 1-hydroxy-7 Azabenzotriazole, HOBt is 1-hydroxybenzotriazole, LAH is lithium aluminum hydride (LiAlH ₄ ), LDA is lithium diisopropylamide, MeCN is acetonitrile, MeOH is methanol, NMM is N-methylmorpholine (4-methylmorpholine), NMP is N-methylpyrrolidin-2-one, TEA is triethylamine, TFA is trifluoroacetic acid, THF is tetrahydrofuran, THP is tetrahydropyranyl, TTFH is fluoro-N, N, N ′, N′-tetramethylformamidinii Um hexafluorophosphate, 9-BBN is 9-borabicyclo [3.3.1] nonane, CDCl ₃ is deuterium chloroform, CD ₃ OD tetradeuterium methanol and DMSO-d ₆ is hexadeuterium dimethyl sulfoxide.

  The present invention relates to compounds of the general formula I specified in the appended claims. The compounds of the present invention are structurally different from known compounds.

  The present invention relates to the use of such compounds in therapy, and in particular to pharmaceutical compositions comprising such compounds.

  In another embodiment, the invention relates to a method of treatment comprising administering an effective amount of one or more compounds of formula I to a subject in need of treatment.

  In a further embodiment, the invention relates to the use of a compound of formula I in the manufacture of a medicament.

Because of the interaction with the histamine H3 receptor, the compounds of the invention as defined in the appended claims and throughout the specification have a wide range of states in which interaction with the histamine H3 receptor is effective and Useful for the treatment of disorders. Thus, the compounds can also find use in the treatment of diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal tract, and endocrine system, for example.
In one embodiment, the invention relates to compounds of the general formula I

｛式中、Ｗ、Ｘ、Ｙ、Ｚは、互いに独立に、式-Ｃ(Ｒ¹)＝又は-Ｎ＝(つまり、窒素)の一部であり、ただし１〜２(それ以上ではない)の記号Ｗ、Ｘ、Ｙ又はＺは、部分-Ｎ＝でなければならず；Ｒ¹は、水素又はＣ_1-3アルキルであり、Ｖは-Ｎ＜又は-ＣＨ＜であり、Ａは結合又はアルキレンリンカー-(ＣＨ₂)_n-であり、ここでｎは、１〜３であり、ただしＡが結合である場合、Ｖは-ＣＨ＜でなくてはならず、Ｒはエチル、プロピル、分岐状Ｃ_3-6アルキル環状Ｃ_3-8アルキルであり、ｍは１、２又は３であり、ｎは１、２又は３であり、Ｄは、ハロゲン、ヒドロキシ、シアノ、Ｃ_1-6-アルキル、Ｃ_3-8-シクロアルキル、Ｃ_1-6-アルコキシ、-(ＣＨ₂)_O-(Ｃ＝Ｏ)_p-ＮＲ²Ｒ³で場合により置換されるヘテロアリールであり、又はＤは、水素、ハロゲン、ヒドロキシ、シアノ、Ｃ_1-6-アルキル、Ｃ_3-8-シクロアルキル、ハロ-Ｃ_1-6-アルキル、Ｃ_1-6-アルコキシ、ハロ-Ｃ_1-6-アルコキシ、Ｃ_1-6-アルキルスルホニル、Ｃ_1-6-アルキルスルフィニル、ヘテロシクリル、ヘテロシクリル-Ｃ_1-6アルキル、ヘテロシクリル-Ｃ_1-6-アルコキシ、ヘテロシクリルカルボニル、Ｃ_1-6-アルキルカルボニル、Ｃ_1-6-アルコキシカルボニル、Ｃ_1-6-アルキルカルボキシ、シアノ-Ｃ_1-6-アルキル、ヒドロキシ-Ｃ_1-6-アルキル、Ｃ_1-6-アルコキシ-Ｃ_1-6-アルキル、Ｃ_1-6-アルキルカルボニルアミノ、Ｃ_1-6-アルキルカルボニルアミノ-Ｃ_1-6アルキル、アリールカルボニルアミノ、アリールカルボニル-アミノ-Ｃ_1-6-アルキル、ヘテロアリールカルボニルアミノ又はヘテロアリールカルボニルアミノ-Ｃ_1-6-アルキル、-(ＣＨ₂)_O-(Ｃ＝Ｏ)_P-ＮＲ²Ｒ³から独立に選ばれる１又は複数の基で場合により置換されるアリールであり、そしてｏは０(ゼロ)、１、２又は３であり、ｐは０(ゼロ)又は１であり、そしてＲ²及びＲ³は、独立に水素、Ｃ_1-6-アルキル又はＣ_3-8-シクロアルキルであるか；又はＲ²とＲ³は結合された窒素と一緒になってヘテロシクリル基を形成する)で表される化合物、又はその塩若しくは溶媒和物。
２)Ｒがイソプロピル、シクロブチル、シクロペンチル又は３-ペンチルである、項目１に記載の化合物。
３)Ｒがイソプロピル又はシクロブチルである、項目１又は２に記載の化合物。
４)ｍが１である、項目１〜３のいずれか一項に記載の化合物。
５)ｍが２である、項目１〜４のいずれか一項に記載の化合物。
６)Ｖが＞ＣＨ-である、項目１〜５のいずれか一項に記載の化合物。
７)Ｖが＞Ｎ-である、項目１〜６のいずれか一項に記載の化合物。
８)Ａが結合又はメチレン(-ＣＨ₂-)である、項目１〜７のいずれか一項に記載の化合物。
９)Ａがメチレンである、項目１〜８のいずれか一項に記載の化合物。
１０)Ｗ、Ｘ、Ｙ及びＺのうちの１つのみが窒素であり、そしてその他の３が各々-ＣＨ＝である、項目１〜９のいずれか一項に記載の化合物。 Preferred features of the invention are as follows:
1) Compounds of general formula I:

{Wherein W, X, Y, Z are, independently of one another, part of the formula -C (R ¹ ) = or -N = (ie nitrogen), provided that it is 1-2 (but not more) The symbol W, X, Y or Z of R must be a moiety —N═; R ¹ is hydrogen or C _1-3 alkyl, V is —N <or —CH <, and A is a bond Or an alkylene linker — (CH ₂ ) _n —, where n is 1-3, but when A is a bond, V must be —CH <, R is ethyl, propyl, Branched C _3-6 alkyl cyclic C _3-8 alkyl, m is 1, 2 or 3, n is 1, 2 or 3, D is halogen, hydroxy, cyano, C _1-6- Alkyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy, heteroaryl optionally substituted with — (CH ₂ ) _O — (C═O) _p —NR ² R ³ , or D is Hydrogen, halogen Hydroxy, cyano, C _1-6 - alkyl, C _3-8 - cycloalkyl, halo -C _1-6 - alkyl, C _1-6 - alkoxy, halo -C _1-6 - alkoxy, C _1-6 - alkyl Sulfonyl, C _1-6 -alkylsulfinyl, heterocyclyl, heterocyclyl-C _1-6 alkyl, heterocyclyl-C _1-6 -alkoxy, heterocyclylcarbonyl, C _1-6 -alkylcarbonyl, C _1-6 -alkoxycarbonyl, C _{1 -6} -alkylcarboxy, cyano-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl, C _1-6 -alkylcarbonylamino, C _{1- 6-} alkylcarbonylamino-C _1-6 alkyl, arylcarbonylamino, arylcarbonyl-amino-C _1-6 -alkyl, heteroarylcarbonylamino or heteroarylcarbonylamino-C _1-6 -alkyl,- (CH ₂ ) _O — (C═O) _P —NR ² R ³ is aryl optionally substituted with one or more groups independently selected from o, and o is 0 (zero), 1, 2, or 3 P is 0 (zero) or 1 and R ² and R ³ are independently hydrogen, C _1-6 -alkyl or C _3-8 -cycloalkyl; or R ² and R ³ Are combined with the bound nitrogen to form a heterocyclyl group), or a salt or solvate thereof.
2) The compound according to item 1, wherein R is isopropyl, cyclobutyl, cyclopentyl or 3-pentyl.
3) The compound according to item 1 or 2, wherein R is isopropyl or cyclobutyl.
4) The compound according to any one of Items 1 to 3, wherein m is 1.
5) The compound according to any one of Items 1 to 4, wherein m is 2.
6) The compound according to any one of Items 1 to 5, wherein V is> CH-.
7) The compound according to any one of Items 1 to 6, wherein V is> N-.
8) The compound according to any one of Items 1 to 7, wherein A is a bond or methylene (—CH ₂ —).
9) The compound according to any one of Items 1 to 8, wherein A is methylene.
10) The compound according to any one of items 1 to 9, wherein only one of W, X, Y and Z is nitrogen and the other 3 are each —CH═.

11) The compound according to any one of items 1 to 10, wherein two of W, X, Y and Z are each nitrogen and the other two are each —CH═.
12) The compound according to any one of Items 1 to 11, wherein W, X, Y and Z are —CH═, ═CH—, ═N— and —CH═, respectively.
13) The compound according to any one of Items 1 to 12, wherein W, X, Y and Z are each —CH═, ═CH—, ═CH— and —N═.
14) The compound according to any one of Items 1 to 13, wherein W, X, Y, and Z are —CH═, ═CH—, ═N—, and —N═, respectively.
15) D is formyl, acetyl, anilino, amino, cyano, diisopropylcarbonyl, ethylsulfonyl, fluoro, methyl-carbonylamino, 4-methylpiperazinylcarbonyl, morpholin-4-yl, morpholin-4-ylcarbonyl, morpholine- 4-ylsulfonyl, N, N-diethylaminocarbonyl, N, N-diethylaminomethyl, N, N-di-methylaminocarbonyl, N, N-dimethylaminomethyl, N, N-dimethylaminosulfonyl, piperidinylsulfonyl, Item which is phenyl substituted by 1 or 2 substituents selected from the group consisting of methylenedioxy when substituted with pyrrolidinylcarbonyl, pyrrolidinylethyl, pyrrolidinylmethyl or 2 different carbon atoms The compound as described in any one of 1-14.
16) D is formyl, amino, cyano, ethylsulfonyl, fluoro, methylcarbonylamino, 4-methylpiperazinylcarbonyl, morpholin-4-yl, morpholin-4-ylcarbonyl, morpholin-4-ylmethyl, morpholine-4- Yl-sulfonyl, N, N-diethylaminocarbonyl, N, N-diethylaminomethyl, N, N-dimethylamino-carbonyl, N, N-dimethylaminomethyl, N, N-dimethylaminosulfonyl, piperidinylsulfonyl, pyrrolidini With phenyl substituted by 1 or 2 substituents selected from the group consisting of methylenedioxy when substituted on two different carbon atoms in the phenyl ring. The compound according to any one of Items 1 to 15, wherein
17) The compound according to any one of items 1 to 16, wherein D is pyridyl substituted with a methyl or oxo group.
18) D is 4-N-acetylphenyl, 4-formylphenyl, 4-anilinophenyl, 4-aminophenyl, 1,3-benzodioxol-5-yl, 4-carboxyphenyl, 4-cyanophenyl 4- (diisopropylcarbonyl) phenyl, 4- (N, N-diethylamino-carbonyl) phenyl, 4- (N, N-diethylaminomethyl) phenyl, 3- (N, N-dimethylaminocarbonyl) -phenyl, 4- (N, N-dimethylaminocarbonyl) phenyl, 4- (N, N-dimethylaminomethyl) phenyl, 4- (N, N-dimethylaminosulfonyl) phenyl, 4-ethylsulfonylphenyl, 4- (methylcarbonylamino) -Phenyl, 1-methyl-2-oxopyridin-5-yl, 4- (4-methylpiperidin-1-ylcarbonyl) phenyl, 2-methyl-pyridin-4-yl, 4-morpholin-4-ylphenyl, 4- (morpholin-4-ylcarbonyl) phenyl, 4- (morpholin-4-ylmethyl) phenyl, 4- (morpholin-4-ylsulfonyl) phenyl, 1-methyl-2-oxo-1,2-dihydropyrida-5 -Yl, 4- (piperidin-1-ylsulfonyl) phenyl, 4- (piperidin-1-ylcarbonyl) phenyl, 4- (pyrrolidin-1-yl-carbonyl) -3-fluorophenyl, 4- (pyrrolidine-1) 18. The compound according to any one of items 1 to 17, which is -ylcarbonyl) phenyl, 4- (pyrrolidin-1-ylethyl) phenyl or 4- (pyrrolidin-1-ylmethyl) phenyl.
19) D is 4-formylphenyl, 4-aminophenyl, 1,3-benzodioxol-5-yl, 4-carboxyphenyl, 4-cyanophenyl, 4- (N, N-diethylaminocarbonyl) phenyl, 4- (N, N-diethylaminomethyl) phenyl, 3- (N, N-dimethylaminocarbonyl) phenyl, 4- (N, N-dimethylaminocarbonyl) phenyl, 4- (N, N-dimethylaminomethyl) phenyl ) Phenyl, 4- (N, N-dimethylaminosulfonyl) phenyl, 4-ethylsulfonylphenyl, 4- (methyl-carbonylamino) phenyl, 1-methyl-2-oxopyridin-5-yl, 4- (4- Methylpiperidin-1-ylcarbonyl) -phenyl, 2-methylpyridin-4-yl, 4-morpholin-4-ylphenyl, 4- (morpholin-4-ylcarbonyl) phenyl, 4- (morpholin-4-ylsulfonyl) ) Phenyl 1-Methyl-2-oxo-1,2-dihydropyrida-5-yl, 4- (piperid-1-yl-sulfonyl) phenyl, 4- (piperid-1-ylcarbonyl) phenyl, 4- (pyrrolidine-1- Ylcarbonyl) -3-fluorophenyl, 4- (pyrrolidin-1-ylcarbonyl) phenyl, 4- (pyrrolidin-1-ylethyl) phenyl or 4- (pyrrolidin-1-yl-methyl) phenyl 19. A compound according to any one of 18.
20) Items 1-19 wherein D is 2-methyl-4-pyridyl, N-methyl-2-oxo-5-pyridyl-, 5-methoxy-3-pyridyl, or 3,4-methylenedioxy-phenyl The compound as described in any one of these.
21) Use of the compound according to any one of items 1 to 20 as a medicine.
22) Use of a compound according to any one of items 1 to 21 as a medicament for curing or preventing any one of the diseases mentioned herein.

Specific examples of compounds of formula I are:
1) 5-1,3-Benzodioxol-5-yl-1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro-2,4′-bipyridinyl;
2) 1′-isopropyl-5- (4-morpholin-4-ylphenyl) -1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl;
3) 1-isopropyl-2'-methyl-1,2,3,4,5,6-hexahydro- [4,2 ';5', 4 '] terpyridine;
4) 5- (4-Ethansulfonylsulfonyl) -1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl;
5) 4- (1′-Isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) -N, N-dimethylbenzamide;
6) [2-Fluoro-4- (1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) phenyl] pyrrolidine -1-ylmethanone;
7) 3- (1′-Isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) -N, N-dimethylbenzamide;
8) N, N-diethyl-4- (1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) benzamide;
9) [4- (1′-Isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) phenyl]-(4-methyl -Piperazin-1-yl) methanone;
10) 1′-Isopropyl-1-methyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro-1H- [3,3 ′; 6 ′, 4 ′] terpyridin-6-one ;
11) [4- (1′-Isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) phenyl] pyrrolidin-1-yl -Methanone;
12) 1′-Isopropyl-5- [4- (piperidine-1-sulfonyl) phenyl] -1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl;
13) 3- (4-ethanesulfonylphenyl) -6- (1-isopropylpiperidin-4-yl) pyridazine;
14) [4- (1′-Cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) phenyl]-(4-methyl -Piperazin-1-yl) methanone;
15) 4- (1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) -N, N-dimethylbenzamide;
16) 4- (1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) -N, N-diethylbenzamide;
17) [4- (1′-Cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) phenyl] pyrrolidin-1-yl -Methanone;
18) 4- [6- (1-Isopropylpiperidin-4-yl) pyridazin-3-yl] -N, N-dimethylbenzenesulfonamide;
19) 3- (1-Isopropylpiperidin-4-yl) -6- (2-methylpyridin-4-yl) pyridazine;
20) 5- [6- (1-Isopropylpiperidin-4-yl) pyridazin-3-yl] -1-methyl-1H-pyridin-2-one;
21) 1′-cyclobutyl-5- (4-ethanesulfonylphenyl) -1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl;
22) 4- (1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) -N, N-dimethylbenzene- Sulfonamide;
23) 1-cyclobutyl-2′-methyl-1,2,3,4,5,6-hexahydro- [4,2 ′; 5 ′, 4 ″] terpyridine;
24) [4- (1′-Cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) benzyl] pipetylamine;
25) 1′-cyclobutyl-5- (4-pyrrolidin-1-ylmethylphenyl) -1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl;
26) [4- (1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) benzyl] dimethylamine;
27) {4- [6- (1-Cyclobutylpiperidin-4-ylmethyl) pyridin-3-yl] phenyl}-(4-methylpiperazin-1-yl) -methanone;
28) 4- [6- (1-Cyclobutylpiperidin-4-ylmethyl) pyridin-3-yl] -N, N-dimethylbenzenesulfonamide;
29) 6- (1-Cyclobutylpiperidin-4-ylmethyl) -2'-methyl- [3,4 '] bipyridinyl;
30) 4- [6- (1-Cyclobutylpiperidin-4-ylmethyl) pyridin-3-yl] -N, N-dimethylbenzamide;
31) {4- [6- (1-Cyclobutylpiperidin-4-ylmethyl) pyridin-3-yl] phenyl} morpholin-4-ylmethanone;
32) {4- [6- (1-Cyclobutylpiperidin-4-ylmethyl) pyridin-3-yl] benzyl} dimethylamine;
33) 2- (1-Cyclobutylpiperidin-4-ylmethyl) -5- (4-ethanesulfonylphenyl) pyridine;
34) N- {4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] phenyl} acetamide;
35) 4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] phenylamine;
36) 1- [6- (4-ethanesulfonylphenyl) pyridin-3-ylmethyl] -4-isopropylpiperazine;
37) 1-Isopropyl-4- {6- [4- (piperidine-1-sulfonyl) phenyl] pyridin-3-ylmethyl} piperazine;
38) 5- (4-Isopropylpiperazin-1-ylmethyl) -2'-methyl- [2,4 '] bipyridinyl;
39) 1- (6-1,3-benzodioxol-5-ylpyridin-3-ylmethyl) -4-isopropylpiperazine;
40) 4- {4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] phenyl} morpholine;
41) 4- [6- (4-Cyclobutylpiperazin-1-ylmethyl) pyridin-3-yl] -N, N-dimethylbenzamide;
42) 4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridin-3-yl] -N, N-dimethylbenzamide;
43) 1-cyclobutyl-4- [5- (4-ethanesulfonylphenyl) pyridin-2-ylmethyl] piperazine;
44) 1- [5- (4-ethanesulfonylphenyl) pyridin-2-ylmethyl] -4-isopropylpiperazine;
45) {4- [6- (4-Cyclobutylpiperazin-1-ylmethyl) pyridin-3-yl] phenyl}-(4-methylpiperazin-1-yl) -methanone;
46) {4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridin-3-yl] phenyl}-(4-methylpiperazin-1-yl) -methanone;
47) {4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] phenyl}-(4-methylpiperazin-1-yl) -methanone;
48) 4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] -N, N-dimethylbenzenesulfonamide;
49) 4- {4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] benzenesulfonyl} morpholine;
50) 1-cyclobutyl-4- {5- [4- (2-pyrrolidin-1-ylethyl) phenyl] pyridin-2-ylmethyl} piperazine;
51) 1-Isopropyl-4- {5- [4- (2-pyrrolidin-1-ylethyl) phenyl] pyridin-2-ylmethyl} piperazine;
52) 1-cyclobutyl-4- [5- (4-pyrrolidin-1-ylmethylphenyl) pyridin-2-ylmethyl] piperazine;
53) 4- [6- (4-Cyclobutylpiperazin-1-ylmethyl) pyridin-3-yl] benzonitrile;
54) 4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridin-3-yl] benzonitrile;
55) 4- [6- (4-Cyclobutylpiperazin-1-ylmethyl) pyridin-3-yl] benzaldehyde;
56) 4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] -N, N-dimethylbenzamide;
57) 4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridazin-3-yl] -N, N-dimethylbenzenesulfonamide;
58) 4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridazin-3-yl] -N, N-dimethylbenzamide;
59) {4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridazin-3-yl] phenyl} morpholin-4-ylmethanone;
60) 3- (4-Ethansulfonylsulfonyl) -6- (4-isopropylpiperazin-1-ylmethyl) pyridazine;
61) {4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridazin-3-yl] phenyl} piperidin-1-ylmethanone;
62) {4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridazin-3-yl] phenyl}-(4-methylpiperazin-1-yl) -methanone and 63) 1-isopropyl-4- [5 -(4-Pyrrolidin-1-ylmethylphenyl) pyridin-2-ylmethyl] piperazine and, in one embodiment, the invention specifically relates to each of these individual compounds. In another aspect, the invention relates to pharmaceutically acceptable salts of each of these compounds, more specifically to the specific salts mentioned in the specific examples below.

  Combining one or more embodiments described herein, optionally with one or more appended claims, results in further embodiments, and the invention is directed to such embodiments and patents. It relates to all possible combinations of the claims.

  In one aspect, the invention provides the use of a compound according to formula I in a pharmaceutical composition. The pharmaceutical composition may, in another aspect of the invention, comprise at least one compound of formula I as an active ingredient together with one or more pharmaceutically acceptable carriers or excipients. In another aspect, the invention provides a pharmaceutical composition in unit dosage form comprising from about 0.05 mg to about 1000 mg, such as from about 0.1 mg to about 500 mg, such as from about 0.5 mg to about 200 mg of a compound of formula I. provide.

  In another aspect, the invention provides the use of a compound of formula I as defined above for the manufacture of a pharmaceutical composition for the treatment of diseases and disorders in which inhibition of H3 histamine receptor has an advantageous effect. .

  In another aspect, there is provided the use of a compound of formula I for the manufacture of a pharmaceutical composition having histamine H3 antagonist activity or histamine H3 inverse agonist activity.

  In another aspect, the invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for weight loss.

  In another aspect, the invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the treatment of overweight or obesity.

  In another aspect, the invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition that suppresses appetite or induces saturation.

  In another aspect, the present invention relates to disorders and diseases associated with overweight or obesity, such as dyslipidemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancers such as endometrial cancer, breast cancer, There is provided the use of a compound of formula I for the manufacture of a pharmaceutical composition for the prevention and / or treatment of disorders and diseases associated with prostate cancer and colon cancer.

  In another aspect, the invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the prevention and / or treatment of eating disorders such as bulimia or bulimia.

  In another aspect, the invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the prevention and / or treatment of IGT (impaired glucose tolerance).

  In another aspect, the invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the prevention and / or treatment of type 2 diabetes.

  In another aspect, the invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the delaying or prevention of progression from IGT to type 2 diabetes.

  In another aspect, the invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the delay or prevention of progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.

  In another aspect, the invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the treatment of diseases and disorders for which stimulation of H3 histamine receptors has an advantageous effect.

  In another aspect, the invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition having histamine H3 agonist activity.

  In another aspect, the invention provides a pharmaceutical composition for the preparation of a pharmaceutical composition for delaying or preventing the progression from allergic nasal catarrh, ulcer, or anorexic non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes. The use of the compound is provided.

  In another aspect, the invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the treatment of Alzheimer's disease, narcolepsy, attention deficit disorder, reduced wakefulness or sleep control.

  In another aspect, the invention relates to the use of a compound of formula I for the manufacture of a pharmaceutical preparation for the treatment of airway disorders such as asthma, gastric acid secretion control or diarrhea.

  In another aspect, the invention provides a method of treating a disorder or disease associated with the H3 histamine receptor, wherein the method is defined above in an effective amount to a subject in need of treatment. Or a method comprising administering a pharmaceutical composition comprising such a compound.

  In another aspect, the present invention provides the above method, wherein an effective amount of a compound of general formula I as defined above is from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg, and more Methods are provided that preferably range from about 0.5 mg to about 500 mg.

  In one aspect, the present invention relates to compounds that inhibit histamine H3 receptor antagonist activity or inverse agonist activity and are therefore useful in the treatment of a wide range of conditions and disorders where inhibition of histamine H3 receptor is advantageous.

  In another aspect, the invention provides a method for weight loss comprising administering to a subject in need of treatment an effective amount of a compound of formula I as defined above.

  In another aspect, the invention provides a method of treating overweight or obesity, comprising administering an effective amount of a compound of formula I to a subject in need of treatment.

  In another aspect, the invention provides a method of appetite suppression or satiety induction, comprising administering an effective amount of a compound of formula I to a subject in need of treatment.

  In another aspect, the invention relates to overweight or obesity such as dyslipidemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancers such as endometrial cancer, breast cancer, prostate cancer and colon cancer. A method for prevention and / or treatment comprising administering an effective amount of a compound of formula I to a subject in need of treatment.

  In another aspect, the invention is a method for the prevention and / or treatment of eating disorders, such as bulimia or bulimia, comprising administering an effective amount of a compound of formula I to a subject in need of treatment. I will provide a.

  In another aspect, the invention provides a method of treating IGT (Glucose Tolerance) comprising administering an effective amount of a compound of Formula I to a subject in need of treatment.

  In another aspect, the invention provides a method of treating type 2 diabetes, comprising administering an effective amount of a compound of formula I to a subject in need of treatment.

  In another aspect, the invention provides a method for delaying or preventing progression from IGT to type 2 diabetes, comprising administering an effective amount of a compound of formula I to a subject in need of treatment. Provide a method.

  In another aspect, the invention provides a method for delaying or preventing the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes, wherein the compound of formula I is effective in a subject in need of treatment. A method is provided comprising administering an amount.

  In another aspect, the invention relates to compounds that exhibit histamine H3 receptor agonist activity and thus may be useful in the treatment of a wide range of conditions and disorders where histamine H3 receptor activation is useful.

  The compounds of the present invention may be useful for the treatment of airway disorders (eg asthma), as an antidiarrheal agent and for the modulation of gastric acid secretion.

  Furthermore, the compounds of the invention may be used for the treatment of diseases associated with the regulation of sleep and wakefulness and for the treatment of narcolepsy and attention deficit disorders.

  Furthermore, the compounds of the present invention may be used as CNS agonists or sedatives.

  The compounds of the present invention may be used to treat conditions associated with epilepsy. Furthermore, the compounds of the present invention may be used for the treatment of motion sickness and dizziness. Furthermore, the compounds of the present invention may be useful as regulators of hypothalamic pituitary secretion, as antidepressants, as regulators of cerebral blood circulation, and in the treatment of irritable bowel syndrome.

  Furthermore, the compounds of the present invention may be useful for the treatment of dementia and Alzheimer's disease.

  The compounds of the present invention may also be useful for the treatment of allergic rhinitis, ulcers or anorexia nervosa.

  The compounds of the invention may be useful in the treatment of migraine (see, for example, The Journal of Pharmacology and Experimental Therapeutics 1998 287, 43-50), as well as in the treatment of myocardial infarction [Expert Opinion on Investigational Drugs (2000); 9: 2537-2542).

  In a further aspect of the invention, treatment of a patient with a compound of the invention is combined with diet and / or exercise.

  In a further aspect of the invention, one or more compounds of the invention are administered in combination with one or more further active agents in any suitable ratio. Such additional active agents are, for example, anti-obesity drugs, anti-diabetic drugs, anti-lipidemic drugs, antihypertensive drugs, therapeutic agents for complications arising from or related to diabetes, resulting from or related to obesity May be selected from drugs for the treatment of complications and disorders.

  Thus, in a further aspect of the invention one or more compounds of the invention may be administered in combination with one or more antiobesity agents or appetite regulating agents. Such drugs include, for example, CART (cocaine amphetamine-regulated transcript) agonist, NPY (neuropeptide Y) antagonist, MC4 (melanocortin 4) agonist, MC3 (melanocortin 3) agonist, orexin antagonist, TNF (tumor necrosis factor) agonist CRF (corticotropin releasing factor) agonist, CRF BP (corticotropin releasing factor binding protein) antagonist, urocortin agonist, β3 adrenergic agonist, such as CL-316243, AJ-9677, GW-0604, LY36284, LY377267 or AZ-40140, MSH (Melanocyte stimulating hormone) agonist, MCH (melanocyte-concentrating hormone) antagonist, CCK (cholecystokinin) agonist, serotonin reuptake Inhibitors such as fluoxetine, seroxat or citalopram, serotonin and noradrenaline reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormones, growth factors such as Prolactin or placental lactogen, growth hormone releasing compound, TRH (thyroid stimulating hormone releasing hormone) agonist, UCP2 or 3 (uncoupled protein 2 or 3) modulator, leptin agonist, DA agonist (bromocriptine, doplexin), lipase / amylase inhibitor, PPAR (peroxisome proliferator activated receptor) modulator, RXR (retinoid X receptor) modulator, TRβ agonist, AGRP (Agouti-related receptor) Park protein) inhibitors, opioid antagonists (e.g. naltrexone), Ekusejin -4 may be selected from GLP-1 and the group consisting of ciliary neurotrophic factor.

In one embodiment of the invention, the antiobesity agent administered in combination with one or more compounds of the invention is leptin.
In another embodiment, such an anti-obesity agent is dextroamphetamine or amphetamine.
In another embodiment, such an anti-obesity agent is fenfluramine or dexfenfluramine.
In yet another embodiment, such an anti-obesity agent is sibutramine.
In a further embodiment, such an antiobesity agent is orlistat.
In another embodiment, such an antiobesity agent is mazindol or phentermine.
In yet another embodiment, such an anti-obesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.

In a further aspect of the invention, one or more compounds of the invention may be administered in combination with one or more antidiabetic agents. Related antidiabetic agents are insulin, insulin analogues and derivatives disclosed in EP 0 792 290 (Novo Nordisk A / S), eg N ^εB29 tetradecanoyldes (B30) human insulin, EP 0 214 826 and EP 0 705 Derivatives disclosed in 275 (Novo Nordisk A / S), for example Asp ^B28 human insulin, derivatives disclosed in US 5,504,188, for example Lys ^B28 Pro ^B29 human insulin, derivatives disclosed in EP 0 368 187 (Aventis), for example Lantus® (all of which are incorporated herein by reference), as well as GLP-1 derivatives, such as those disclosed in WO 98/08871 (Novo Nordisk A / S), which is hereby incorporated by reference As well as orally active hypoglycemic drugs).

  Orally active hypoglycemic agents preferably act on imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, α-glucosidase inhibitors, β-cell ATP-dependent potassium channels Agents disclosed in, for example, potassium channel openers, WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A / S), which are incorporated herein by reference. Or mitiglinide, or potassium channel blockers such as BTS-67582, nateglinide, glucagon antagonists such as WO 99/01423 and WO 00/39088 (Novo Nordisk A / S and Agouron Pharmaceuticals, Inc.), both of which are GLP-1 agonists such as WO 00/42026 (Novo Nordisk A / S and Agouron Pharmaceuticals, Inc.) (which is hereby incorporated by reference). Inhibition of liver enzymes involved in stimulation of gluconeogenesis and / or glycogenolysis, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors Agents, GSK-3 (glycogen synthase kinase 3) inhibitors, lipid metabolism, lipid metabolism-regulating compounds such as antihyperlipidemic drugs, compounds that reduce food intake, PPAR (peroxisome proliferator activated receptor) and RXR (Retinoid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.

In one embodiment of the invention, one or more compounds of the invention are insulin or an insulin analogue or derivative, such as N ^{εB29 -tetradecanoyldes} (B30) human insulin, Asp ^B28 human insulin, Lys ^B28 Pro ^B28 human insulin. , Lantus®, or a mixed preparation containing one or more of these.

  In a further embodiment of the invention, one or more compounds of the invention may be administered in combination with a sulfonylurea such as tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide.

  In another embodiment of the invention, one or more compounds of the invention may be administered in combination with a biguanide, such as metformin.

  In yet another embodiment of the invention, one or more compounds of the invention may be administered in combination with a meglitinide, such as repaglinide or nateglinide.

  In yet another embodiment of the present invention, one or more compounds of the present invention are thiazolidinedione insulin sensitizers such as troglitazone, siglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011 / CI -1037 or T174, or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292, all of which are incorporated herein by reference. They may be administered in combination.

  In yet another embodiment of the present invention, one or more compounds of the present invention are insulin sensitizers such as GI262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW -409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516, or WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192 or WO 00 / 63193 or WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00 / It may be administered in combination with a compound disclosed in 63190 or WO 00/63189 (Novo Nordisk A / S), all of which are hereby incorporated by reference.

  In a further embodiment of the invention, one or more compounds of the invention may be administered in combination with an alpha glucosidase inhibitor such as voglibose, emiglitate, miglitol or acarbose.

  In another embodiment of the invention, one or more compounds of the invention are administered in combination with an agent that acts on the ATP-dependent potassium channel of beta cells, for example tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide May be.

  In yet another embodiment of the invention, one or more compounds of the invention may be administered in combination with nateglinide.

  In yet another embodiment, one or more compounds of the invention are antidyslipidemic or antihyperlipidemic agents such as cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextro It may be administered in combination with thyroxine.

  In yet another embodiment of the present invention, one or more compounds of the present invention are combined with an anti-hyperlipidemic drug such as cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine. May be administered.

  In another aspect of the present invention, one or more compounds of the present invention are combined with more than one of the above compounds, for example, metformin and sulfonylureas such as glyburide; sulfonylureas and acarbose; nateglinide and metformin; Metformin; sulfonylurea, metformin and troglitazone; insulin and sulfonylurea; insulin and metformin; insulin, metformin and sulfonylurea; insulin and troglitazone; insulin and lovastatin;

  Furthermore, one or more compounds of the present invention may be administered in combination with one or more antihypertensive drugs. Examples of antihypertensive drugs are beta blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channels Blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and beta blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

  Any suitable combination of a compound described in the present invention with diet and / or exercise, one or more of the above compounds, and optionally one or more other active substances is considered within the scope of the present invention. I want to understand that.

  The compounds of the present invention may be chiral, and any enantiomer as a separated, pure or partially purified enantiomer or racemic mixture is included within the scope of the present invention. Intended.

  Furthermore, diastereomers can form when double bonds or fully or partially saturated ring systems or bonds with more than one asymmetric center or limited rotation are present in the molecule. Any diastereomers as separated, pure or partially purified diastereomers or mixtures thereof are intended to be included within the scope of the present invention.

  Furthermore, some of the compounds of the invention may exist in different tautomeric forms and any tautomeric form that the compounds can form are included within the scope of the invention.

  The present invention also includes pharmaceutically acceptable salts of the compounds of the present invention. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid and the like. Representative examples of suitable inorganic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid , Mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid , Stearic acid, palmitic acid, EDTA, glycolic acid, paraaminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2. Examples of metal salts include lithium salts, sodium salts, potassium salts, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium salts, methyl ammonium salts, dimethyl ammonium salts, trimethyl ammonium salts, ethyl ammonium salts, hydroxyethyl ammonium salts, diethyl ammonium salts, butyl ammonium salts, tetramethyl ammonium salts, and the like. .

  Pharmaceutically acceptable acid addition salts are hydrates that the compounds of the present invention can form.

  Acid addition salts may be obtained as direct products of compound synthesis. Alternatively, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt is isolated by evaporating the solvent or otherwise isolated by separating the salt and solvent. It is.

  The compounds of the present invention may form solvents with standard low molecular weights using methods well known to those skilled in the art. Such solvates are to be understood as being within the scope of the present invention.

  The invention also encompasses prodrugs of the compounds of the invention which undergo chemical transformation by metabolic processes after administration and then become active pharmaceutical substances. In general, such prodrugs will be functional derivatives of the compounds of this invention that are readily converted in vivo to the target compound of formula I. Conventional methods for selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodorugs” H. Bundgaard, Edsevier, 1985.

  The present invention includes active metabolites of the compounds of the present invention.

  Further embodiments can be obtained by combining one or more individual embodiments described herein, optionally with one or more of the embodiments of the respective claims, and the present invention is directed to such embodiments. It relates to all possible combinations of the claimed aspects.

In one embodiment, the present invention provides compounds of Formula I as provided herein, wherein R ¹ is hydrogen, C _1-6 -alkyl, C _2-6 -alkenyl, C _3-8 -cycloalkyl or C _3-8 cycloalkyl-C _1-6 -alkyl; R ² is hydrogen or C _1-6 -alkyl; or R ¹ and R ² together with the atoms to which they are attached, nitrogen Containing rings, optionally forming other heterocyclyl groups; m is 0, 1 or 2; one of the four substituents of R ³ , R ⁴ , R ⁵ and R ⁶ is halogen, hydroxy, When either cyano or C _1-6 -alkyl and ^three of the four substituents of R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen, X is —S— In other embodiments, the invention relates to the use of such compounds as medicaments, and further embodiments In a manner, the present invention relates to the use of such compounds for the treatment of any specific disease referred to herein or any particular disease referred to herein.

Pharmaceutical Compositions The compounds of the present invention may be administered alone, in one or multiple doses, or may be administered in combination with a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition according to the present invention may be formulated with a pharmaceutically acceptable carrier or diluent, and any other known adjuvants and excipients according to conventional techniques, such as Remington: The It may be formulated as disclosed in Science and Practice of Pharmacy, 19th edition, edited by Gennaro mack Publishing Co., Easton, PA, 1995. The pharmaceutical composition may be any suitable route, e.g. oral, rectal, nasal, pulmonary, topical (e.g. buccal and sublingual), transdermal, intracapsular, intraperitoneal, vaginal or parenteral (e.g. subcutaneous, intramuscular). , Intrathecal, intravenous and intradermal) routes may be specifically formulated for administration, with the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.

  Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the pharmaceutical composition can be prepared with a coating, such as an enteric coating, or the pharmaceutical composition can be prepared by controlled release of the active ingredient, such as by methods well known in the art. Accordingly, it can be formulated to provide sustained or sustained release.

  Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

  Pharmaceutical compositions for parenteral administration include sterile injectable aqueous solutions and sterile nonaqueous injectable solutions, dispersions, suspensions or emulsions, and sterile powders that are reconstituted in sterile injectable solutions or dispersions before use. It is done. It should be understood that depot injectable formulations are within the scope of the present invention.

  Other suitable dosage forms include suppositories, sprays, ointments, creams, gels, inhalants, transdermal patches, implants and the like.

  Typical oral doses range from about 0.001 to about 100 mg / kg body weight per day, preferably from 0.01 to about 50 mg / kg body weight, and more preferably from about 0.05 to about 10 mg / kg body weight. Yes, administered in one or more single doses, eg 1-3 doses. The exact dose will be apparent to those skilled in the art of frequency and mode of administration, sex, age weight, and general condition of the subject being treated, the nature and severity of the condition being treated, and the complications being treated It depends on the factors.

  The formulation may conveniently be provided in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration of one or more times per day, such as 1 to 3 times per day, is 0.05 to 1000 mg, preferably about 0.1 to about 500 mg, and more preferably about 0. From 0.5 mg to about 200 mg of a compound of the invention (or a salt or derivative thereof as described above) may be included.

  For parenteral routes such as intravenous, intrathecal, intramuscular, and similar administrations, typical doses are on the order of approximately half of those used for oral administration.

  The compounds of the invention are generally used as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having a free base functional group. Where the compound of formula I contains a free base functionality, such salts are pharmaceutically acceptable (acid-base equivalent) pharmaceutically acceptable solutions or suspensions of the free base form of the compound of formula I. Prepared in a conventional manner by treatment with acid. Representative examples of related inorganic and organic acids are described above. Physiologically acceptable salts of the compounds of the present invention having a hydroxyl group include the anion of the compound in combination with a suitable cation, such as sodium or ammonium ion.

  For parenteral administration, solutions of the novel compounds of formula I in sterile aqueous solution, aqueous propylene glycol or sesame oil or peanut oil may be used. Such aqueous solutions should be appropriately buffered as needed, and the liquid diluent is first made isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The aqueous medium used can be utilized by standard techniques known to those skilled in the art.

  Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, clay, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipid, fatty acid fatty acid amine, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of Formula I with pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed route of administration. The formulation may conveniently be present in unit dosage form by methods known in the pharmaceutical art.

  Formulations of the present invention suitable for oral administration may exist as discrete units, such as capsules or tablets, each containing a predetermined amount of the active ingredient, and appropriate excipients. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as a water-in-oil or oil-in-water liquid emulsion.

  When a solid carrier is used for oral administration, the formulation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier may vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable solution, such as an aqueous or non-aqueous suspension or solution.

  A typical tablet that can be prepared by conventional tablet technology consists of 5.0 mg of a compound of the invention, 67.8 mg lactose, Ph. Eur., 31.4 mg microcrystalline cellulose (Avicel) in the core, 1.0 mg Amberlite® IRP88 (ie polacrilin potassium NF, tablet disintegrant, Rohm and Haas) and magnesium stearate PH. Eur. Qs, about 9 mg hydroxypropyl methylcellulose and about 0.9 mg Mywacet 9 -40T (acylated monoglyceride used as plasticizer for film coating) with coating.

  If desired, the pharmaceutical composition of the invention may comprise a compound of formula I in combination with one or more additional pharmaceutically active substances, such as those selected from those described above.

  All references cited in this specification, including publications, patent applications, and patents, are all incorporated by reference individually and specifically as if each reference had been incorporated herein. To the extent (to the maximum extent permitted by law).

  All headings and subheadings are used herein for convenience only and should not be construed as limiting the invention in any way.

  The use of some or all of the specific examples or exemplary words (e.g., “such as”) provided herein is intended to provide a better understanding of the invention and is not claimed elsewhere. If not, then does not limit the scope of the invention. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

  The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and / or legal enforceability of such patent documents. Citation of a reference is not an admission that the reference constitutes prior art.

  In this specification, the phrase “comprise” should be interpreted broadly to mean “include”, “contain”, or “comprehend” (EPO Guidelines C4 .13).

  This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

  The following examples are provided by way of illustration and not by way of limitation. The representative examples mentioned below are specific embodiments of the present invention.

  Briefly described, the compounds of the invention can be prepared in a manner known per se or in a manner analogous to known processes.

General Experimental Methods NMR spectra were obtained from 5 mm selective inverse (SEI, ¹ H and ¹³ C), 5 mm broadband inverse (BBI, ¹ H, broadband) and 5 mm quadronuclide (QNP, ¹ H, ¹³ C) probe beads. 300 and 400 MHz Bruker DRX300, Avance300DRX400 or AV400 apparatus equipped with Chemical shift (δ) is given in units of parts per million (ppm) on the low magnetic field side of tetramethylsilane as an internal standard.

HPLC method A
Hibar ™ RT 250-4, Lichosorb ™ RP-18, 5.0 μm, 4.0 × 250 mm column; gradient, 20% -80% solvent B (acetonitrile with 0.1% TFA ), Solvent A (water containing 0.1% TFA), within 30 minutes, 1.0 ml / min, detection at 210 nm, temperature 30 ° C., Merck-Hitachi series 7000 system (Merck-Hitachi pump L -7100 and Merck-Hitachi autosampler L-7200 or Rheodyne sample injector).

HPLC method B
Waters XTerra ™ PrepRP ₁₈ , 10 μm, 30 mm × 150 mm column; gradient: solvent A (water containing 0.05% TFA) with 5% to 95% solvent B (acetonitrile), within 15 minutes, 40 mL / min RP purification was performed on a Gilson system (3 Gilson 306 pump, Gilson 170 DAD detector and Gilson 215 liquid handler) using 210 nm detection at room temperature. Pooled fractions were evaporated to dryness under suction or evaporated under suction until acetonitrile was removed, then frozen and lyophilized.

HPLC method C
YMC-ODS, 5.0 μm, 4.6 × 50 mm column; elution gradient, solvent A (water containing 0.1% TFA) with 0-30% solvent B (acetonitrile containing 0.1% TFA) Within 6 minutes, and then for 2 minutes, 2.5 mL / min, detection at 220 nm, RP analysis was performed on a Shimadzu LC-20 using a temperature of 30 ° C.

HPLC method D
YMC-ODS, 5.0 μm, 4.6 × 50 mm column; elution gradient, solvent A (water containing 0.1% TFA) with 0-60% solvent B (acetonitrile containing 0.1% TFA) RP analysis was performed on a Shimadzu LC-20, maintained at 2.5 mL / min, within 8 min, then 2 min, detected at 220 nm, temperature 30 ° C.

HPLC method E
YMC-ODS, 5.0 μm, 4.6 × 50 mm column; elution gradient, solvent A (water containing 0.1% TFA) with 10% -80% solvent B (acetonitrile containing 0.1% TFA) RP analysis was performed on Shimadzu using a detection at 220 nm and a temperature of 30 ° C., within 6 minutes, and then maintained at 2.5 mL / min for 2 minutes.

HPLC method F
Luna, 5 μm, 21.2 mm × 250 mm column; elution gradient, solvent A (water containing 0.1% TFA) with 5-30% solvent B (acetonitrile containing 0.1% TFA), within 15 minutes RP purification was performed on a Gilson Gebula Series system using 80 mL / min, detection at 220 nm, temperature 25 ° C., injection volume 30 ml. The pooled fractions were evaporated until the acetonitrile was removed under suction and then frozen and dried.

HPLC-MS Method G
Column: Waters Xterra MSC-18 × 3 mm, id. Buffer: 4 min linear gradient 5% -95%, acetonitrile, 0.01% TFA, flow rate 1.0 ml / min, detection at 210 nm (diode array detector Analog output from), MS detection ionization mode API-ES, scan 100-1000 amu step 0.1 amu.

When electromagnetic wave synthesis microwave synthesis was applied, the reaction solution was heated by irradiating an electromagnetic wave into a sealed electromagnetic wave container in a single mode Emrys Optimizer EXP manufactured by Personal Chemistry (trademark).

  The following examples and general methods described herein describe intermediate compounds and final products of general formula I identified in the specification and synthetic schemes. The preparation of the compounds of general formula I according to the invention is described in detail using the following examples. The reaction may not apply as described for each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognized by those skilled in the art. In this case, the reaction can be carried out successfully by routinely known changes known to the person skilled in the art, such changes appropriately protecting interfering groups, changing to other conventional reagents, or This is done by changing the reaction conditions as usual. Alternatively, other reactions that are disclosed herein or that are customary when not disclosed are applicable to the preparation of the corresponding compounds of the invention. In all preparation methods, all starting materials are known or may be prepared by one skilled in the art as well as preparation of similar known compounds, or according to the general formulas A to N described herein. It may be prepared. The following examples are given by way of illustration and are not limiting.

General manufacturing method A
A compound of formula I, wherein Y and / or W is —N═ and R, D, and X are each as defined in formula I} (named as compound Ia): Can be manufactured as outlined in:

As defined herein, an amine of formula A-1 is catalyzed by a metal complex such as [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloro-methane complex. In the coupling reaction, a halogen of the formula A-2 {wherein each of D, X, Y, Z and W is as defined herein and Hal represents chlorine or bromine} Reaction with substituted heteroaryl affords compounds of formula Ia. The reaction can be carried out in a suitable solvent with a base such as t-BuONa, NaOH, TEA, K ₂ CO ₃ or Na ₂ CO ₃ , such as DMSO, THF, DMA, DMF, at the maximum reflux temperature. The compound of formula A-1 is a Zn derivative of an amine as defined herein and can also be synthesized by known methods.

  Compounds of formula A-2 can be prepared according to known methods described in WO03 / 066604A2, Tetrahedron 2000, 56, 9655-9662, and Tetrahedron Lett. 2001, 42, 2779-2781.

本明細書に定義される式Ｂ-１のアミンを、ＴＨＦ中において９-ＢＢＮと室温〜最大で還流温度で反応させて、［１,１'-ビス(ジフェニルホスフィノ)フェロセン］ジクロロパラジウム(ＩＩ)-ジクロロメタン又はＰｄ(ｄｐｐｆ)Ｃｌ₂ジクロロメタン複合体などの金属複合体により触媒されるカップリング反応で、式Ｂ-２のハロゲン置換されたヘテロアリール｛式中、Ｄ、Ｘ、Ｙ、Ｚ、及びＷは、それぞれ本明細書に定義されるとおりであり、そしてＨａｌは塩素又は臭素を表す｝と反応して、式Ｉａの化合物を生成する。当該反応は、ｔ-ＢｕＯＮａ、ＮａＯＨ、ＴＥＡ、Ｋ₂ＣＯ₃又はＮａ₂ＣＯ₃などの塩基を伴うジメチルスルホキシド、テトラヒドロフラン、ジメチルアセトアミド、ジメチル-ホルムアミドなどの適切な溶媒中で、還流温度で反応を行うことができる。式Ｂ-１の化合物において、Ｐｇは、本明細書に定義されるアミンのＢｏｃ又はＣｂｚ保護誘導体を意味し、これらは以下の文献：S. Vice et. al. JOC, 2001, 66, 2487-2492及び Bioorg. Med. Chem. Lett. 2003,13,2167-2172にしたがって合成することができる。 General manufacturing method B
Compound of formula Ib {wherein Y and / or W is -N = and A is methylene and B, D and X are each as defined in formula I} (the compound is hereinafter represented by formula Ib Can be prepared as outlined below:

An amine of formula B-1 as defined herein is reacted with 9-BBN in THF at room temperature up to reflux temperature to give [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium ( II) -halogenated heteroaryls of formula B-2 in a coupling reaction catalyzed by a metal complex such as dichloromethane or Pd (dppf) Cl ₂ dichloromethane complex, wherein D, X, Y, Z And W are each as defined herein and Hal represents chlorine or bromine} to form a compound of formula Ia. The reaction is carried out at reflux temperature in a suitable solvent such as dimethyl sulfoxide, tetrahydrofuran, dimethylacetamide, dimethyl-formamide with a base such as t-BuONa, NaOH, TEA, K ₂ CO ₃ or Na ₂ CO _3. It can be carried out. In the compound of formula B-1, Pg means a Boc or Cbz protected derivative of an amine as defined herein and these are: S. Vice et. Al. JOC, 2001, 66, 2487- 2492 and Bioorg. Med. Chem. Lett. 2003, 13, 2167-2172.

本明細書で定義される式Ｃ-１のアミンの化合物は、室温〜最大還流温度でＴＨＦ中において９-ＢＢＮと反応し、さらに[１,１'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(ＩＩ)-ジクロロメタン又はＰｄ(ｄｐｐｆ)Ｃｌ２ジクロロメタン複合体などの金属複合体により触媒されるカップリング反応において、式Ｃ-２のハロゲン置換ヘテロアリール｛式中、Ｄ、Ｘ、Ｙ、Ｚ及びＷはそれぞれ本明細書に定義されるとおりであり、そしてＨａｌが塩素又は臭素を表す｝と反応して、式Ｉｃの化合物を与える。この反応は、適切な溶媒、例えば、ｔ-ＢｕＯＮａ、ＮａＯＨ、ＴＥＡ、Ｋ₂ＣＯ₃又はＮａ₂ＣＯ₃などの塩基を伴うジメチルスルホキシド、テトラヒドロフラン、ジメチルアセトアミド、ジメチルホルムアミドなどの適切な溶媒中で行われてもよい。式Ｃ-１の化合物は、本明細書に定義されるアミンのＢｏｃ又はＣｂｚ保護誘導体であってもよく、そして文献：S. Vice et. al .in JOC, 2001, 66, 2487- 2492、及びBioorg. Med. Chem. Lett. 2003, 13, 2167-2172にしたがって合成することができる。 General method C
A compound of formula Ic wherein Y and / or W is -N = and A is methylene;
B, D and X are each as defined in Formula I} (the compound is hereinafter referred to as Formula Ic) can be prepared as outlined below:

The amine compound of formula C-1 as defined herein reacts with 9-BBN in THF at room temperature to maximum reflux temperature, and further [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium. In a coupling reaction catalyzed by a metal complex such as (II) -dichloromethane or Pd (dppf) Cl 2 dichloromethane complex, a halogen-substituted heteroaryl of formula C-2 wherein D, X, Y, Z and W Are each as defined herein and react with Hal for chlorine or bromine to give a compound of formula Ic. This reaction is carried out in a suitable solvent such as t-BuONa, NaOH, TEA, dimethyl sulfoxide with a base such as K ₂ CO ₃ or Na ₂ CO ₃ , tetrahydrofuran, dimethylacetamide, dimethylformamide and the like. It may be broken. The compound of formula C-1 may be a Boc or Cbz protected derivative of an amine as defined herein, and the literature: S. Vice et. Al. In JOC, 2001, 66, 2487-2492, and Bioorg. Med. Chem. Lett. 2003, 13, 2167-2172.

本明細書で定義される式Ｉｂの保護アミンは、室温〜最大還流温度でＴＨＦ、ジクロロメタン又はジエチルエーテルなどの溶媒中のＨＣｌ、ＨＢｒ、又はＴＦＡなどと反応させて、式Ｉｄ１の化合物を脱保護することができる。式Ｉｃ１のアミン｛式中、Ｙ及び／又はＷは-Ｎ＝、Ｄ、Ｘであり、そして各々は式Ｉについて定義されるとおりであり、還元剤の存在下においてケトン又はアルデヒドと反応させて、式Ｉｄの化合物を与えてもよい。この反応は、適切な溶媒、例えば水、メタノール、テトラヒドロフラン又は１,２-ジクロロエタン中で最大でも還流温度で行われてもよい。還元剤は、例えばＮａＣＮＢＨ₃又はＮａＢＨ(ＯＡｃ)₃であってもよく、最終的に例えば酢酸などの酸触媒の存在してもよい。式Ｉｂの化合物は、Bioorg. Med. Chem. Lett. 2003、13、2167-2172, 及びJ. Med Chem. Chim. Ther. 1991, 26, 6, 625-637に記載される一般的方法に従って製造することもできる。 General method D
A compound of formula Id, wherein Y and / or W is -N =, and D and X are each as defined in formula I} (the compound is hereinafter referred to as formula Ic) is Can be manufactured as outlined:

A protected amine of formula Ib as defined herein is reacted with HCl, HBr, or TFA, etc. in a solvent such as THF, dichloromethane or diethyl ether at room temperature to maximum reflux temperature to deprotect the compound of formula Id1 can do. Amines of formula Ic1 wherein Y and / or W are —N═, D, X, and each is as defined for formula I, reacted with a ketone or aldehyde in the presence of a reducing agent. May give compounds of formula Id. This reaction may be carried out at a maximum at reflux temperature in a suitable solvent such as water, methanol, tetrahydrofuran or 1,2-dichloroethane. The reducing agent may be, for example, NaCNBH ₃ or NaBH (OAc) ₃ , and finally an acid catalyst such as acetic acid may be present. Compounds of formula Ib are prepared according to the general methods described in Bioorg. Med. Chem. Lett. 2003, 13, 2167-2172, and J. Med Chem. Chim. Ther. 1991, 26, 6, 625-637. You can also

本明細書に定義される式Ｅ-１の保護アミンを、ｔ-ＢｕＯＮａ、ＮａＯＨ、ＴＥＡ、Ｋ₂ＣＯ₃又はＮａ₂ＣＯ₃を伴うメタノール、ジメチルスルホキシド、テトラヒドロフラン、ジメチルアセトアミド、ジメチルホルムアミド、又は１,２-ジクロロエタン中で、最大で還流の温度にて、式Ｅ-２で表される化合物｛式中、Ｙ及び／又はＷが-Ｎ＝であり、かつＤ、Ｘが各々式Ｉに定義されるとおりであり、そしてＨａｌが塩素、臭素又はトリフルオロスルホネートである｝と反応させて、式Ｉｅの化合物を形成する。
式Ｅ２の化合物は、J. Med. Chem. 1992, 35, 3, 438-450; J. Heterocycl. Chem. 1986, 23, 149-152;及び J. Med. Chem. SIR 2005, 48, 5, 1367-1383に記載される一般的方法に従って調製することができる。 General method E
A compound of formula Id, wherein Y and / or W is —N═, D and X are each as defined in formula I} (the compound is named formula Ie) is outlined below. Can be manufactured as:

A protected amine of formula E-1 as defined herein is methanol, dimethyl sulfoxide, tetrahydrofuran, dimethylacetamide, dimethylformamide, or 1 with t-BuONa, NaOH, TEA, K ₂ CO ₃ or Na ₂ CO ₃ , 2-dichloroethane, at a maximum reflux temperature, a compound of formula E-2 wherein Y and / or W is -N = and D and X are each defined in formula I And Hal is chlorine, bromine or trifluorosulfonate} to form a compound of formula Ie.
Compounds of formula E2 are described in J. Med. Chem. 1992, 35, 3, 438-450; J. Heterocycl. Chem. 1986, 23, 149-152; and J. Med. Chem. SIR 2005, 48, 5, It can be prepared according to the general method described in 1367-1383.

式Ｆ-１の化合物｛式中、Ａ、Ｒ、Ｖ、Ｘ、Ｙ、Ｗ及びＺはそれぞれ本明細書に定義されるとおりであり、そしてＨａｌは塩素、臭素、又はヨウ素を表す｝は、式Ｆ-２のボロン酸誘導体又は対応するボロン酸エステル誘導体｛ここでＤは本明細書に定義されるとおりである｝と反応して、式ｌｉの化合物を与える。反応は、適切な溶媒、例えばアセトニトリル／水中で、最大１５０℃にて、適切な触媒、例えばビストリフェニルホスフィンパラジウム(ＩＩ)ジクロリド及び炭酸ナトリウムの存在下で行うことができる。この反応は、ハロゲン及びボロン酸部分が互換性を有する試薬から始めて反応を行うこともできる。当該反応は、上に記載されるのと同様の条件下で行われてもよい。 General method F
Compounds of formula I, wherein A, B, X, Y, W, Z and D are each as defined in formula I} (name the compounds as formula li) are outlined below. Can be manufactured as:

A compound of formula F-1 wherein A, R, V, X, Y, W and Z are each as defined herein and Hal represents chlorine, bromine or iodine} is: Reaction with a boronic acid derivative of formula F-2 or a corresponding boronate ester derivative, where D is as defined herein, provides a compound of formula li. The reaction can be carried out in a suitable solvent such as acetonitrile / water at a maximum of 150 ° C. in the presence of a suitable catalyst such as bistriphenylphosphine palladium (II) dichloride and sodium carbonate. This reaction can also be carried out starting with a reagent in which the halogen and boronic acid moieties are compatible. The reaction may be performed under conditions similar to those described above.

ステップ１：
５-１,３-［ベンゾジオキソール-５-イル］-３',４',５',６'-テトラヒドロ-２'Ｈ-２,４'-ビピリジニル-１'-カルボン酸ｔｅｒｔ-ブチルエステル,ジヒドロクロリド：

５-ブロモ-３',４',５',６'-テトラヒドロ-２'Ｈ-［２,４'］ビピリジニル-１'-カルボン酸ｔｅｒｔ-ブチル・エステル(０.３３ｇ、０.９７ｍｍｏｌ)、ボロン酸(０.１８ｇ、１.０６ｍｍｏｌ)、ビス(トリフェニルホスフィン)パラジウム(ＩＩ)クロリド(０.０３２ｇ、０.０４６ｍｍｏｌ)、１ＭのＮａ₂ＣＯ₃(４ｍｌ)及びアセトニトリル(４ｍｌ)を、５ｍｌ電磁波バイアル中に混合した。反応混合液を８０℃で１０００秒加熱した。ＬＣ-ＭＳは、より多くの開始物質を示したので、加熱をさらに８０℃で２０００秒続けた。２つの相を分離し、アセトニトリル相を蒸発させ、そして粗生成物をシリカゲルカラム上で、ＥｔＯＡｃ／ヘプタン(１：４)を溶出液として用いて精製した。収率：２５０ｍｇの白色結晶(６８％)、ＬＣ-ＭＳ(エレクトロスプレー)：ｍ／ｚ：３８３(Ｍ＋１)、Ｒｔ＝１.４７分であった。 Example 1 (general method A)
5- [1,3-Benzodioxol-5-yl] -1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro-2,4′-bipyridinyl, dihydro Chloride:

Step 1 :
5-1,3- [Benzodioxol-5-yl] -3 ', 4', 5 ', 6'-tetrahydro-2'H-2,4'-bipyridinyl-1'-tert-butyl carboxylate Esters, dihydrochloride:

5-bromo-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester (0.33 g, 0.97 mmol), Boronic acid (0.18 g, 1.06 mmol), bis (triphenylphosphine) palladium (II) chloride (0.032 g, 0.046 mmol), 1M Na ₂ CO ₃ (4 ml) and acetonitrile (4 ml) in 5 ml Mixed in electromagnetic wave vial. The reaction mixture was heated at 80 ° C. for 1000 seconds. LC-MS showed more starting material, so heating continued for an additional 2000 seconds at 80 ° C. The two phases were separated, the acetonitrile phase was evaporated and the crude product was purified on a silica gel column using EtOAc / heptane (1: 4) as eluent. Yield: 250 mg of white crystals (68%), LC-MS (electrospray): m / z: 383 (M + 1), Rt = 1.47 min.

５-１,３-ベンゾジオキソール-５-イル-３',４',５',６'-テトラヒドロ-２'Ｈ-２,４'-ビピリジニル-１'-カルボン酸ｔｅｒｔ-ブチルエステル(０.２５０ｇ、０.６５ｍｍｏｌ)を、ＤＣＭ(１２ｍｌ)に溶解し、ＴＦＡ(３ｍｌ)を加え、そして反応混合液を室温で２時間撹拌した。水及び１Ｎ・ＮａＯＨを加え、ＤＣＭ相を洗浄し、そしてＮａ₂ＳＯ₄で乾燥させた。蒸発させることにより、１５０ｍｇの白色結晶化合物を与えた(８１％)。
¹H NMR(300MHz, CDCl₃)δ:8.8(1H, s), 8.5(2H, d), 8.3(1H, br s), 7.1(d,d, 2H), 6.95(d,d, 1H), 6.1(s,H), 3.6-3.7(m, 3H), 3.2-3.4(2H), 2.4(m, 2H), 2.2-2.3(2H, m), 1.55(1H, s). Step 2 :
5-1,3-benzodioxol-5-yl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro-2,4′-bipyridinyl:

5-1,3-benzodioxol-5-yl-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H-2,4′-bipyridinyl-1′-carboxylic acid tert-butyl ester ( 0.250 g, 0.65 mmol) was dissolved in DCM (12 ml), TFA (3 ml) was added and the reaction mixture was stirred at room temperature for 2 hours. Water and 1N NaOH were added, the DCM phase was washed and dried over Na ₂ SO ₄ . Evaporation gave 150 mg of white crystalline compound (81%).
¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.8 (1H, s), 8.5 (2H, d), 8.3 (1H, br s), 7.1 (d, d, 2H), 6.95 (d, d, 1H) , 6.1 (s, H), 3.6-3.7 (m, 3H), 3.2-3.4 (2H), 2.4 (m, 2H), 2.2-2.3 (2H, m), 1.55 (1H, s).

Step 3 :
5-1,3-benzodioxol-5-yl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro-2,4′-bipyridinyl (0.15 g, 0.53 mmol) Was dissolved in THF (4 ml) and water (10 μl), propanone (70 μl, 0.8 mmol), acetic acid (100 μL) and 1M sodium cyanoborohydride in THF (80 μL, 0.8 mmol) were added. . The mixture was stirred at 60 ° C. overnight.

LC-MS showed a lot of starting material, a lot of propanone (70 μL, 0.8 mmol), so THF containing 1 M sodium cyanoborohydride (80 μL, 0.8 mmol) was added. Further stirring at room temperature left much starting material. Propanone (70 μL, 0.8 mmol) and THF containing 1 M sodium cyanoborohydride (80 μL, 0.8 mmol) were added. Stir overnight at room temperature. 1N HCl (1 ml) was added and the reaction mixture was purified by preparative Gilson (HPLC method B). Product containing fractions were evaporated and 1M HCl (3 ml) was added and evaporated. Basified with 1M NaOH (3 ml) and extracted with DCM. The organic phase was evaporated and 1m HCl (1ml) was added. The dihydrochloride of the title compound was isolated as yellow crystals.
¹ H NMR (300 MHz, MeOH-D4) δ: 9.00 (d, J = 2.02 Hz, 1H) 8.82 (dd, J = 8.59, 2.53Hz, 1H) 8.09 (d, J = 8.59Hz, 1H) 7.35- 7.36 (m, 1H) 7.32-7.34 (m, 1H) 7.03 (d, J = 8.59Hz, 1H) 6.08 (s, 2H) 3.49-3.71 (m, 4H) 3.32-3.37 (m, 2H) 2.32-2.42 (m, 4H) 1.45 (d, J = 6.57Hz, 6H).
LC-MS (electrospray): m / z: 325 (M + 1) Rt = 0.8 min (Method D)

ステップ１：
５-(４-モルホリノ-４-イルフェニル)-３',４',５',６'-テトラヒドロ-２'Ｈ-［２,４'］ビピリジニル-１'-カルボン酸ｔｅｒｔ-ブチルエステル：

５-ブロモ-３',４',５',６'-テトラヒドロ-２'Ｈ-［２,４'］ビピリジニル-１'-カルボン酸ｔｅｒｔ-ブチルエステル(０.６ｇ、１.８ｍｍｏｌ)、４-モルホリニルフェニルボロン酸(４００ｍｇ、１.９ｍｍｏｌ)、ビス(トリフェニルホスフィン)-パラジウム(ＩＩ)クロリド(０.０６ｇ、０.０９ｍｍｏｌ)、１ＭのＮａ₂ＣＯ₃(４ｍｌ)及びアセトニトリル(４ｍｌ)を、５ｍｌの電磁波バイアル中に混合した。反応混合液を８５℃で１５００秒間加熱した。水層を取り除いた。アセトニトリル相をろ過し、そして蒸発させた。ヘプタン：ＥｔＯＡｃ(１：１)を溶出剤として用いて、残りをシリカゲルカラムで精製した。７３０ｍｇ(９８％)を遊離塩基として単離した。
ＬＣ-ＭＳ(エレクトロスプレー)：ｍ／ｚ：４２４(生成物)及び(ＢＯＣを有さない生成物)３２４ Example 2 (general method A)
1′-Isopropyl-5- (4-morpholin-4-ylphenyl) -1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl, dihydrochloride:

Step 1 :
5- (4-morpholino-4-ylphenyl) -3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester:

5-Bromo-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester (0.6 g, 1.8 mmol), 4 -Morpholinylphenylboronic acid (400 mg, 1.9 mmol), bis (triphenylphosphine) -palladium (II) chloride (0.06 g, 0.09 mmol), 1M Na ₂ CO ₃ (4 ml) and acetonitrile (4 ml) ) Was mixed in a 5 ml electromagnetic wave vial. The reaction mixture was heated at 85 ° C. for 1500 seconds. The aqueous layer was removed. The acetonitrile phase was filtered and evaporated. The residue was purified on a silica gel column using heptane: EtOAc (1: 1) as eluent. 730 mg (98%) was isolated as the free base.
LC-MS (electrospray): m / z: 424 (product) and (product without BOC) 324

５-(４-モルホリノ-４-イルフェニル)-３',４',５',６'-テトラヒドロ-２'Ｈ-［２,４'］ビピリジニル-１'-カルボン酸ｔｅｒｔ-ブチルエステル(０.３７ｇ、０.８７４ｍｍｏｌ)を、ＤＣＭ(１２ｍｌ)中で溶解し、ＴＦＡ(４ｍＬ)を加え、そして開始物質が消えるまで反応混合物を１時間撹拌した。水及び１ＮのＮａＯＨを、ｐＨ＝１２になるまで加え、ＤＣＭ(４×４０ｍｌ)で抽出後、Ｎａ₂ＣＯ₃でＤＣＭ相を乾燥させ、そして蒸発させて、２８０ｍｇ(１００％)の白色結晶を得た。
¹H NMR (300 MHz, CDCl₃) δ: 8.75(d, 1H); 7.75(d,d, 1H), 7.5(d,d,2H), 7.2(d, 1H), 6.9(d, 2H), 3.9(m, 4H), 3.2(m, 6H), 2.7-2.9(m, 3H), 1.95(br, d, 2H), 1.6-2.05(m, 2H), 1.55(br s, 2H). Step 2 :
5- (4-morpholino-4-ylphenyl) -1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl:

5- (4-morpholino-4-ylphenyl) -3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester (0 .37 g, 0.874 mmol) was dissolved in DCM (12 ml), TFA (4 mL) was added and the reaction mixture was stirred for 1 hour until the starting material disappeared. Water and 1N NaOH are added until pH = 12, after extraction with DCM (4 × 40 ml), the DCM phase is dried over Na ₂ CO ₃ and evaporated to give 280 mg (100%) of white crystals. Obtained.
¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.75 (d, 1H); 7.75 (d, d, 1H), 7.5 (d, d, 2H), 7.2 (d, 1H), 6.9 (d, 2H) , 3.9 (m, 4H), 3.2 (m, 6H), 2.7-2.9 (m, 3H), 1.95 (br, d, 2H), 1.6-2.05 (m, 2H), 1.55 (br s, 2H).

Step 3 :
5- (4-morpholino-4-ylphenyl) -1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (0.28 g, 0.87 mmol) , Dissolved in MeOH containing acetic acid (10 ml). Propanone (255 μL, 3.46 mmol) and Na (CN) BH ₃ (109 mg, 1.7 mmol) were added with stirring at room temperature. The reaction mixture was stirred overnight. Propanone (60 μL, 0.87 mmol) and Na (CN) BH ₃ (50 mg, 0.87 mmol) were added and stirring for an additional 3 hours was required to complete the reaction. The reaction mixture was evaporated and 1M HCl (2 ml) methanol (2 ml) and a few drops of DMF were added to dissolve the crude product. Further purification based on preparative HPLC (Method B) gave the title compound as a salt of TFA. The TFA salt was dissolved in MeOH and diethyl ether containing HCl was added. Evaporation under suction gave the title compound as a yellow solid.

LC-MS (electrospray): m / z: 366 (M + 1); Rt = 0.85 min
¹ H NMR (300MHz, MeOH-D4) δ: 9.1 (s, 1H), 8.85 (d, d, 1H), 8.1 (d, 1H), 7.95 (d, 2H); 7.55 (d, 2H), 4.05 (m, 4H), 3.5-3.7 (m, 10H), 2.35 (m, 4H), 1.45 (d, 6H).

Example 3 (General Method A)
1-isopropyl-2 ″ -methyl-1,2,3,4,5,6-hexahydro- [4,2 ′; 5 ′, 4 ″] terpyridine, dihydrochloride:

５-ブロモ-３',４',５',６'-テトラヒドロ-２'Ｈ-［２,４'］ビピリジニル-１'-カルボン酸ｔｅｒｔ-ブチルエステル(０.６ｇ、１.７６ｍｍｏｌ)、２-メチルピリジン-４-ボロン酸(２６４ｍｇ、１.９ｍｍｏｌ)、ビス(トリフェニルホスフィン)-パラジウム(ＩＩ)クロリド(０.０６ｇ、０.０９ｍｍｏｌ)、１Ｍ Ｎａ₂ＣＯ₃(４ｍｌ)及びアセトニトリル(４ｍｌ)を、５ｍｌの電磁波バイアル中で混合した。さらに１Ｍ Ｎａ₂ＣＯ₃(２ｍｌ)及びアセトニトリル(２ｍｌ)を加えた。反応混合液を８５℃で１５００秒間加熱した。水相を取り除いた。アセトニトリル相をＤＣＭ(２０ｍｌ)に加えた。有機相をろ過し、そして吸引下で蒸発させた。粗製混合物を、シリカゲル上でＥｔＯＡｃ／ヘプタン(４：１)を用い、そして次にＥｔＯＡｃ／ヘプタン(９：１)を用いて精製した。生成物を透明オイルとして回収した(５４０ｍｇ、８７％)。 Step 1 :
2 ″ -Methyl-3,4,5,6-tetrahydro-2H- [4,2 ′; 5 ′, 4 ″] terpyridine-1-carboxylic acid tert-butyl ester:

5-Bromo-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester (0.6 g, 1.76 mmol), 2 -Methylpyridine-4-boronic acid (264 mg, 1.9 mmol), bis (triphenylphosphine) -palladium (II) chloride (0.06 g, 0.09 mmol), 1M Na ₂ CO ₃ (4 ml) and acetonitrile (4 ml) ) In a 5 ml electromagnetic wave vial. Further 1M Na ₂ CO ₃ (2 ml) and acetonitrile (2 ml) were added. The reaction mixture was heated at 85 ° C. for 1500 seconds. The aqueous phase was removed. The acetonitrile phase was added to DCM (20 ml). The organic phase was filtered and evaporated under suction. The crude mixture was purified on silica gel with EtOAc / heptane (4: 1) and then with EtOAc / heptane (9: 1). The product was recovered as a clear oil (540 mg, 87%).

LC-MS (electrospray): m / z: 354 (M + 1); Rt = 1.12 min
¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.85 (d, 1H), 8.6 (d, 1H), 7.48 (s, 1H), 7.35 (d, 1H), 7.28 (d, 2H), 4.2 (m, 2H), 2.8 (m, 3H), 2.65 (s, 3H), 1.95 (m, 2H), 1.65-1.8 (m, 2H), 1.5 (d, 9H).

２''-メチル-３,４,５,６-テトラヒドロ-２Ｈ-［４,２'；５',４''］ターピリジン-１-カルボン酸ｔｅｒｔ-ブチルエステル(０.５４ｇ、１.５２８ｍｍｏｌ)を、ＤＣＭ(１２ｍＬ)中に溶解し、ＴＦＡ(４ｍＬ)を加え、反応混合液を室温で２時間撹拌した。ｐＨ＝１２になるまで反応混合液に水及び１Ｎ ＮａＯＨを加えた。有機相を洗浄し、Ｎａ₂ＣＯ₃で乾燥し、ろ過し、そして蒸発させて３１０ｍｇ(８０％)の黄色結晶を得た。
¹H NMR(300MHz, CDCl₃) δ: 8.8(d,d, 1H), 8.55(d, 1H), 7.8(d,d, 1H), 7.4(s, 1H), 7.3(m, 2H), 3.25(br. d, 2H), 2.9(t,t, 1H), 2.8(d,t, 2H), 2.6(s, 3H), 1.9(br.d, 2H), 1.7(m, 2H). Step 2 :
2 ″ -methyl-1,2,3,4,5,6-hexahydro- [4,2 ′; 5 ′, 4 ″] terpyridine:

2 ″ -Methyl-3,4,5,6-tetrahydro-2H- [4,2 ′; 5 ′, 4 ″] terpyridine-1-carboxylic acid tert-butyl ester (0.54 g, 1.528 mmol) Was dissolved in DCM (12 mL), TFA (4 mL) was added and the reaction mixture was stirred at room temperature for 2 h. Water and 1N NaOH were added to the reaction mixture until pH = 12. The organic phase was washed, dried over Na ₂ CO ₃ , filtered and evaporated to give 310 mg (80%) of yellow crystals.
¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.8 (d, d, 1H), 8.55 (d, 1H), 7.8 (d, d, 1H), 7.4 (s, 1H), 7.3 (m, 2H), 3.25 (br.d, 2H), 2.9 (t, t, 1H), 2.8 (d, t, 2H), 2.6 (s, 3H), 1.9 (br.d, 2H), 1.7 (m, 2H).

Step 3 :
2 ″ -methyl-1,2,3,4,5,6-hexahydro- [4,2 ′; 5 ′, 4 ″] terpyridine (0.31 g; 1.22 mmol) was added to 2% edikeles ( eddikesyre) in methanol (10 ml). Propanone (360 uL, 4.9 mmol) and Na (CN) BH ₃ (153 mg, 2.5 mmol) were added. The reaction mixture was stirred overnight at room temperature. LC-MS showed that some starting material remained and additional propanone (90 μL, 1.2 mmol) and Na (CN) BH ₃ (75 mg, 1.2 mmol) were added and stirred for another 3 hours at room temperature. did. The reaction mixture was evaporated under suction and redissolved with 1N HCl (1 ml), MeOH (2 ml), and a few drops of DMF. The mixture was purified based on preparative HPLC (Method D). The TFA salt was isolated. The TFA salt was dissolved in MeOH, dissolved in diethyl ether with HCl and evaporated to give the title compound dihydrochloride as 210 mg (50%) of yellow crystals.

LC-MS (electrospray): m / z: (M + 1); Rt = 0.56 min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.35 (s, 1H), 8.9 (m, 2H), 8.45 (s, 1H), 8.35 (d, 1H), 8.1 (1H), 3.45-3.7 ( m, 5H), 2.9 (s, 3H), 2.3-2.45 (m, 4H), 1.45 (d, 6H).

ステップ１：
５-(４-エタンスルホニルフェニル)-３',４',５',６'-テトラヒドロ-２'Ｈ-［２,４'］ビピリジニル-１'-カルボン酸ｔｅｒｔ-ブチルエステル：

５-ブロモ-３',４',５',６'-テトラヒドロ-２'Ｈ-［２,４'］ビピリジニル-１'-カルボン酸ｔｅｒｔ-ブチルエステル(０.６ｇ、１.８ｍｍｏｌ)、ボロン酸(４１４ｍｇ、１.９ｍｍｏｌ)、ビス(トリフェニルホスフィン)パラジウム(ＩＩ)クロリド(０.０６ｇ、０.０９ｍｍｏｌ)、１ＭのＮａ₂ＣＯ₃(４ｍｌ)及びアセトニトリル(４ｍｌ)を５ｍｌの電磁波バイアル中に混合する。反応混合液を８５℃で１５００秒間加熱した。水相を取り除き、そしてアセトニトリル相をＤＣＭ(２０ｍｌ)に加え、ろ過し、そして吸引下で蒸発させた。粗製反応混合液をシリカゲルカラム上で、ＥｔＯＡｃ：ヘプタン(１：１)を溶出剤として用いて精製した。生成物を油として単離した(７６０ｍｇ、１００％)。 Example 4 (General production method A)
5- (4-ethanesulfonylphenyl) -1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl, dihydrochloride:

Step 1 :
5- (4-Ethansulfonylsulfonyl) -3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester:

5-Bromo-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester (0.6 g, 1.8 mmol), boron Acid (414 mg, 1.9 mmol), bis (triphenylphosphine) palladium (II) chloride (0.06 g, 0.09 mmol), 1M Na ₂ CO ₃ (4 ml) and acetonitrile (4 ml) in a 5 ml electromagnetic vial. To mix. The reaction mixture was heated at 85 ° C. for 1500 seconds. The aqueous phase was removed and the acetonitrile phase was added to DCM (20 ml), filtered and evaporated under suction. The crude reaction mixture was purified on a silica gel column using EtOAc: heptane (1: 1) as eluent. The product was isolated as an oil (760 mg, 100%).

LC-MS (electrospray): m / z: 431 (M + 1); Rt = 1.48 min
¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.8 (d, 1H), 7.9 (d, 2H), 7.85 (d, d, 1H), 7.7 (d, 2H), 7.25 (d, 1H9, 4.25 ( m, 2H), 3.2 (q, 2H), 2.8-2.9 (m, 3H), 1.95 (d, 2H), 1.75 (m, 2H), 1.45 (s, 9H), 1.35 (t, 3H).

５-(４-エタンスルホニルフェニル)-３',４',５',６'-テトラヒドロ-２'Ｈ-［２,４'］ビピリジニル-１'-カルボン酸ｔｅｒｔ-ブチルエステル(０.７６ｇ、１.６７５ｍｍｏｌ)を、ＤＣＭ(１２ｍｌ)に溶解し、そしてＴＦＡ(４ｍｌ)を加えた。反応混合液を４時間撹拌した。１Ｎ ＮａＯＨ(２０ｍｌ)を加え、そしてＤＣＭ相を洗浄し、そしてＮａ₂ＣＯ₃で乾燥し、ろ過し、そして蒸発して４６２ｍｇ(７９％)の白色結晶化合物を与えた。
¹H NMR (300 MHz, CDCl₃) δ: 8.85(s, 1H), 7.95(d, 2H), 7.8(d,d, 1H), 7.7(d, 2H), 7.25(d, 1H), 3.2(m, 2H), 3.15(q, 2H), 2.9(t,t, 1H), 2.7(t,d, 2H), 1.95(m, 2H), 1.7(d,t, 2H), 1.3(t, 3H). Step 2 :
5- (4-ethanesulfonylphenyl) -1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl:

5- (4-ethanesulfonylphenyl) -3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester (0.76 g, 1.675 mmol) was dissolved in DCM (12 ml) and TFA (4 ml) was added. The reaction mixture was stirred for 4 hours. 1N NaOH (20 ml) was added and the DCM phase was washed and dried over Na ₂ CO ₃ , filtered and evaporated to give 462 mg (79%) of white crystalline compound.
^{1 H NMR (300 MHz, CDCl} 3) δ: 8.85 (s, 1H), 7.95 (d, 2H), 7.8 (d, d, 1H), 7.7 (d, 2H), 7.25 (d, 1H), 3.2 (m, 2H), 3.15 (q, 2H), 2.9 (t, t, 1H), 2.7 (t, d, 2H), 1.95 (m, 2H), 1.7 (d, t, 2H), 1.3 (t , 3H).

Step 3 :
5- (4-ethanesulfonylphenyl) -1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (0.462, 1.4 mmol) Dissolved in MeOH (10 mL) containing acetic acid. Propanone (410 μL, 5.6 mmol) and Na (CN) BH ₃ (175 mg, 2.8 mmol) were added. The reaction mixture was stirred overnight at room temperature. LC-MS showed that some starting material remained. A lot of propanone (100 μl, 1.4 mmol) and Na (CN) BH ₃ (88 mg, 1.4 mmol) were added and stirring was continued for another 3 hours. The reaction mixture was evaporated under suction and dissolved in 1M HCl (2 ml), MeOH (2 ml) and a few drops of DMF. The mixture was filtered and purified on preparative HPLC (Method B).
The TFA salt was isolated, redissolved in MeOH, and 1N HCl (10 ml) was added. Evaporation gave the dihydrochloride salt of the title compound as white crystals (300 mg, 50%).

LC-MS (electrospray): m / z: 373 (M + 1); Rt = 0.92 min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.15 (s, 1H), 9.0 (d, 1H), 8.15 (d, 2H), 8.05 (s, 5H), 3.6-3.8 (m, 4H), 3.2-3.4 (6H), 2.35 (m, 4H) 1.45 (d, 6H), 1.25 (t, 3H).

Example 5 (General production method A)
4- (1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) -N, N-dimethylbenzamide, dihydrochloride :

Ｐｄ-ｃａｔ＝［１,１'-ビス(ジフェニルホスフィノ)フェロセン］ジクロロパラジウム(ＩＩ)-ジクロロメタン複合体
ステップ１：
まず４-亜鉛-ヨードピペリジン-１-カルボン酸化合物を合成した。ＤＭＦ中においてＣｅｌｐｕｒｅ Ｐ６５を亜鉛粉と窒素雰囲気下で混合し、そして１,２-ジブロモーメタンに溶解したＴＭＳ-Ｃｌを少しづつ加えた。反応混合液を室温でさらに３０分撹拌した。温度を５８〜６０℃に維持する速度で乾燥ＤＭＥ中に溶解した４-ヨードピペリジン-１-カルボン酸を加えた。全ての変換を確かにするため、反応混合液をさらに３０分間加熱した。この反応混合液を、ＣｅｌｐｕｒｅＰ６５を充填したカラムを通してろ過した後に次のステップに用いた。カラムを抽出体積の乾燥ＤＭＥの洗浄して、全ての物質をカラムから確実に洗い流した。 5-Bromo-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester:

Pd-cat = [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex
Step 1 :
First, 4-zinc-iodopiperidine-1-carboxylic acid compound was synthesized. Celpure P65 was mixed with zinc powder in a DMF under a nitrogen atmosphere, and TMS-Cl dissolved in 1,2-dibromo-methane was added little by little. The reaction mixture was stirred for an additional 30 minutes at room temperature. 4-Iodopiperidine-1-carboxylic acid dissolved in dry DME was added at a rate to maintain the temperature at 58-60 ° C. The reaction mixture was heated for an additional 30 minutes to ensure all conversion. The reaction mixture was filtered through a column packed with Celpure P65 and used in the next step. The column was washed with an extraction volume of dry DME to ensure that all material was flushed from the column.

Step 2 :
2,5-Dibromopyridine (10.26 g, 43.29 mmol) was charged with Cu (I) I (dry) (0.495 g, 2.597 mmol) and Pd-catalyst (1.06 g, 0.03 mmol). Mixed with dry DME (30 ml) to form a slurry. The freshly filtered product from step 1 was added directly to the reaction mixture under N ₂ atmosphere and stirred well. The reaction mixture was heated at 80 ° C. for 18 hours. To the reaction mixture was added 1M NH ₄ Cl / water (100 ml) and washed with brine and dried over MgSO ₄ . Filtration and evaporation under suction gave an oil 6.9 g (48%).

５-ブロモ-３',４',５',６'-テトラヒドロ-２'Ｈ-［２,４'］ビピリジニル-１'-カルボン酸ｔｅｒｔ-ブチルエステル(６.９ｇ、２０.２２ｍｍｏｌ)をＤＣＭに溶解した。いくらかＣＯ₂が放出され、そして反応混合液が僅かに発熱するので、ゆっくり加えた。反応混合液を３５分間撹拌し、溶媒を吸引下で蒸発させた。ジエチルエーテルの添加により、ＴＦＡ塩を白色結晶として与えた。収率：６.５５ｇ(９１％)。
LC-MS(エレクトロスプレー):m/z: 242(M+1), Rt:0,771分
¹H NMR (300 MHz, DMSO-D6) δ: 8.6(d, 1H), 8.0(d,d, 1H), 7.25(d, 1H), 3.5(m, 2H), 3.05(m, 3H), 1.75-2.05(m, 4H). Step 3 :
5-Bromo-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl:

5-Bromo-3 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,4 ′] bipyridinyl-1′-carboxylic acid tert-butyl ester (6.9 g, 20.22 mmol) was converted to DCM. Dissolved in. Some CO ₂ was released and the reaction mixture exothermed slightly and was added slowly. The reaction mixture was stirred for 35 minutes and the solvent was evaporated under suction. Addition of diethyl ether gave the TFA salt as white crystals. Yield: 6.55 g (91%).
LC-MS (electrospray): m / z: 242 (M + 1), Rt: 0,771 min
¹ H NMR (300 MHz, DMSO-D6) δ: 8.6 (d, 1H), 8.0 (d, d, 1H), 7.25 (d, 1H), 3.5 (m, 2H), 3.05 (m, 3H), 1.75-2.05 (m, 4H).

５-ブロモ-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(６.７ｇ、１８.９ｍｍｏｌ)を２％酢酸を含むＭｅＯＨ(４０ｍｌ)中に溶解した。プロパノン(８ｍＬ、１１３ｍｍｏｌ)及びＮａ(ＣＮ)ＢＨ₃(３.６ｇ、５７ｍｍｏｌ)を加えた。反応混合液に１Ｎ・ＨＣｌを加え、そして吸引下で蒸発させた。化合物を水に溶解し、ｐＨをｐＨ＝１２に調製し、そしてＤＣＭで抽出した(３×２００ｍｌ)。ＤＣＭ相をＮａ₂ＣＯ₃で乾燥し、ろ過し、そして蒸発させて、４.４ｇ(８２％)の白色結晶を与えた。
LC-MS(エレクトロスプレー):m/z:284(M+1),Rt=0.89分
¹H NMR(300MHz,DMSO-D6)δ:8.6(d, 1H), 8.45(d,d, 1H), 7.26(d, 1H), 2.85(br. D, 2H), 2.65(p, 1H), 2.6(t, t, 1H), 2.15(d,t, 2H), 1.78(br. D, 2H), 1.65(m, 2H), 0.98(d, 6H). Step 4 :
5-Bromo-1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl:

5-Bromo-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (6.7 g, 18.9 mmol) and 2% acetic acid in MeOH (40 ml) Dissolved in. Propanone (8 mL, 113 mmol) and Na (CN) BH ₃ (3.6 g, 57 mmol) were added. 1N HCl was added to the reaction mixture and evaporated under suction. The compound was dissolved in water, the pH was adjusted to pH = 12, and extracted with DCM (3 × 200 ml). The DCM phase was dried over Na ₂ CO ₃ , filtered and evaporated to give 4.4 g (82%) white crystals.
LC-MS (electrospray): m / z: 284 (M + 1), Rt = 0.89 min
¹ H NMR (300 MHz, DMSO-D6) δ: 8.6 (d, 1H), 8.45 (d, d, 1H), 7.26 (d, 1H), 2.85 (br.D, 2H), 2.65 (p, 1H) , 2.6 (t, t, 1H), 2.15 (d, t, 2H), 1.78 (br. D, 2H), 1.65 (m, 2H), 0.98 (d, 6H).

Step 5 :
5-Bromo-1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (0.400 g, 1.412 mmol), N, N— Di-methylbenzamide-4-boronic acid (0.327 g, 1.2 mmol) and bis (triphenylphosphine) palladium- (II) chloride (50 mg, 0.07 mmol) were added in acetonitrile (4 mL) in an electromagnetic wave vial (20 ml). ) And 1M Na ₂ CO ₃ (4 mL) under N ₂ atmosphere. The reaction mixture was heated at 85 ° C. for 1200 seconds. The reaction mixture was separated and the acetonitrile phase was purified based on preparative HPLC (Method D). Evaporation under suction gave the TFA salt, which was dissolved in MeOH and diethyl ether containing HCL was added. Evaporation under suction gave the dihydrochloride salt as white crystals. 350 mg (58%).
LC-MS (electrospray): m / z: 352 (M + 1), Rt = 1.403 min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.15 (d, J = 2.02 Hz, 1H) 8.94 (dd, J = 8.34, 1.77 Hz, 1H) 8.17 (d, J = 8.59 Hz, 1H) 7.94 ( d, J = 8.08 Hz, 2H) 7.65 (d, J = 8.08 Hz, 2H) 3.48-3.77 (m, 4H) 3.32-3.41 (m, 2H) 3.14 (s, 3H) 3.04 (s, 3H) 2.27- 2.47 (m, 4H) 1.45 (d, J = 6.57 Hz, 6H).

５-ブロモ-１'-イソプロピル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(４００ｍｇ；１.４ｍｍｏｌ)、２-フルオロ-フェニルピロリジン-１-イルメタノン-４ボロン酸(４０１ｍｇ；１.７ｍｍｏｌ)及びビス(トリフェニル-ホスフィン)パラジウム(ＩＩ)クロリド(５０ｍｇ、０.０７ｍｍｏｌ)を、２０ｍｌ電磁波バイアル中の４ｍｌアセトニトリル及び４ｍＬの１Ｍ・Ｎａ₂ＣＯ₃に溶解した。反応混合液を８５℃で１５００秒間加熱した。水相を取り除き、そしてアセトニトリル相に１Ｎ・ＨＣｌ(３ｍｌ)を加え、ろ過し、そして吸引下で蒸発させた。粗製生成物は、アセトニトリル及びＭｅＯＨ中に溶解し、そして調製的ＨＰＬＣ(方法Ｄ)上で精製した。ＴＦＡ塩として生成物を単離した。１ＨＣｌ(５ｍｌ)中に再溶解させ、そして吸引下で２回蒸発させて、標題の化合物を二塩酸塩として与えた。３８２ｍｇ(５８％)結晶。 Example 6 (General production method A)
[2-Fluoro-4- (1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) phenyl] pyrrolidine-1 -Il-methanone, dihydrochloride:

5-Bromo-1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (400 mg; 1.4 mmol), 2-fluoro-phenylpyrrolidine -1-ylmethanone-4-boronic acid (401 mg; 1.7 mmol) and bis (triphenyl-phosphine) palladium (II) chloride (50 mg, 0.07 mmol) were added in 4 ml acetonitrile and 4 ml of 1M Na in a 20 ml electromagnetic vial. Dissolved in ₂ CO ₃ . The reaction mixture was heated at 85 ° C. for 1500 seconds. The aqueous phase was removed and 1N HCl (3 ml) was added to the acetonitrile phase, filtered and evaporated under suction. The crude product was dissolved in acetonitrile and MeOH and purified on preparative HPLC (Method D). The product was isolated as a TFA salt. Redissolved in 1HCl (5 ml) and evaporated twice under suction to give the title compound as the dihydrochloride salt. 382 mg (58%) crystals.

LC-MS (electrospray): m / z: 396 (M + 1), Rt = 0.75 min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.04 (d, J = 2.02 Hz, 1H) 8.59 (d, J = 8.08 Hz, 1H) 7.87 (d, J = 8.08 Hz, 1H) 7.70 (d, J = 9.10 Hz, 2H) 7.61 (t, J = 7.33 Hz, 1H) 3.55-3.72 (m, 5H) 3.38 (t, J = 6.57 Hz, 3H) 3.25-3.33 (m, 2H) 2.17-2.43 (m , 4H) 1.87-2.13 (m, 4H) 1.44 (d, J = 6.57 Hz, 6H)

５-ブロモ-１'-イソプロピル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(４００ｍｇ; １.４ｍｍｏｌ)及びＮ,Ｎ-ジメチルベンズアミド-３-ボロン酸(０.３２７ｇ；１.７ｍｍｏｌ)を反応させ、そして実施例６に記載されるのと同じ様式で精製した。標題の化合物を二塩酸塩、白色結晶として単離した３６８ｍｇ(６１ｇ)。 Example 7 (General production method A)
3- (1′-Isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) -N, N-dimethylbenzamide, dihydrochloride :

5-Bromo-1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (400 mg; 1.4 mmol) and N, N-dimethylbenzamide -3-Boronic acid (0.327 g; 1.7 mmol) was reacted and purified in the same manner as described in Example 6. 368 mg (61 g) of the title compound isolated as dihydrochloride, white crystals.

LC-MS (electrospray): m / z: 352 (M + 1), Rt = 0.78min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.06 (d, J = 2.02 Hz, 1H) 8.74 (dd, J = 8.34, 1.77 Hz, 1H) 8.00 (d, J = 8.59 Hz, 1H) 7.90 ( d, J = 7.58 Hz, 1H) 7.85 (s, 1H) 7.67 (t, J = 7.58 Hz, 1H) 7.59 (d, 1H) 3.54-3.75 (m, 3H) 3.40-3.53 (m, 1H) 3.23- 3.37 (m, 2H) 3.14 (s, 3H) 3.05 (s, 3H) 2.20-2.44 (m, 4H) 1.44 (d, J = 7.07 Hz, 6H).

５-ブロモ-１'-イソプロピル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(４００ｍｇ；１.４ｍｍｏｌ)及びＮ,Ｎ-ジエチルベンズアミド-３-ボロン酸(０.３２７ｇ；１.７ｍｍｏｌ)を反応させ、そして実施例６と同じ様に精製した。標題の化合物を二塩酸塩２００ｍｇ(３３％)白色結晶として単離した。 Example 8 (General production method A)
N, N-diethyl-4- (1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) benzamide, dihydrochloride :

5-Bromo-1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (400 mg; 1.4 mmol) and N, N-diethylbenzamide -3-boronic acid (0.327 g; 1.7 mmol) was reacted and purified as in Example 6. The title compound was isolated as white crystals 200 mg (33%) white crystals.

LC-MS (electrospray): m / z: 380 (M + 1), Rt = 0.99 min
¹ H NMR (300 MHz, MeOH-D4) δ: 10.73 (s, 1H) 9.05 (s, 1H) 8.57 (d, J = 7.07 Hz, 1H) 7.88 (d, J = 8.59 Hz, 2H) 7.74 (d , J = 8.08 Hz, 1H) 7.51 (d, J = 8.08 Hz, 2H) 3.41-3.57 (m, 4H) 3.31-3.40 (m, 2H) 3.19-3.28 (m, 2H) 3.04-3.18 (m, 2H ) 2.27-2.43 (m, 2H) 2.15-2.27 (m, 2H) 1.33 (d, J = 6.57 Hz, 6H) 1.02-1.22 (m, 6H).

５-ブロモ-１'-イソプロピル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(４００ｍｇ；１.４ｍｍｏｌ)及び４-(４-メチルピペラジン-１-カルボニル)フェニルボロン酸,ピナコール・エステル(０.５６ｇ；１.７ｍｍｏｌ)を反応させ、そして実施例６と同様に精製した。標題の化合物を二塩酸塩として２５０ｍｇ(３７％)の白色結晶として単離した。
LC-MS(エレクトロスプレー): m/z: 407 (M+1), Rt=0.50分
¹H NMR (300 MHz, MeOH-D4) δ: 9.16 (s, 1H) 8.96 (d, J=8.29 Hz, 1H) 8.20 (d, J=8.29 Hz, 1H) 7.98 (d, J=7.91 Hz, 2H) 7.73 (d, J=7.54 Hz, 2H) 3.47 - 3.78 (m, 8H) 3.16 - 3.44 (m, 6H) 2.97 (s, 3H) 2.35 - 2.47 (m, 4H) 1.46 (d, J=6.41 Hz, 6H). Example 9 (General production method A)
[4- (1′-Isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) phenyl]-(4-methylpiperazine- 1-yl) methanone, dihydrochloride:

5-Bromo-1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (400 mg; 1.4 mmol) and 4- (4-methyl) Piperazine-1-carbonyl) phenylboronic acid, pinacol ester (0.56 g; 1.7 mmol) was reacted and purified as in Example 6. The title compound was isolated as a dihydrochloride salt as 250 mg (37%) of white crystals.
LC-MS (electrospray): m / z: 407 (M + 1), Rt = 0.50min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.16 (s, 1H) 8.96 (d, J = 8.29 Hz, 1H) 8.20 (d, J = 8.29 Hz, 1H) 7.98 (d, J = 7.91 Hz, 2H) 7.73 (d, J = 7.54 Hz, 2H) 3.47-3.78 (m, 8H) 3.16-3.44 (m, 6H) 2.97 (s, 3H) 2.35-2.47 (m, 4H) 1.46 (d, J = 6.41 Hz, 6H).

５-ブロモ-１'-イソプロピル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(４００ｍｇ；１.４ｍｍｏｌ)及びＮ-メチルピリジン-２-オン-５-ボロン酸ピナコール・エステル(０.３９８ｇ；１.７ｍｍｏｌ)を実施例６と同様に反応させ、そして精製した。標題の化合物をジヒドロクロリドとして１００ｍｇ(１８％)の白色固体として単離した。
LC-MS(エレクトロスプレー): m/z: 312 (M+1), Rt= 0.57分
¹H NMR (300 MHz, MeOH-D4) δ: 9.05(d, １Ｈ), 8.8(d,d,１Ｈ), 8.4(d, １Ｈ), 8.1 (d, １Ｈ), 7.95(d,d,１Ｈ), 6.72(d, １Ｈ), 3.7(s, 3H), 3.4-3.6(m, 4H), 3.3-3.35(m, 2H), 2.3-2.4(m, 4H), 1.4(d, 6H). Example 10 (General production method A)
1 ″ -isopropyl-1-methyl-1 ″, 2 ″, 3 ″, 4 ″, 5 ″, 6 ″ -hexahydro-1H- [3,3 ′; 6 ′, 4 ″ ] Terpyridin-6-one, dihydrochloride:

5-Bromo-1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (400 mg; 1.4 mmol) and N-methylpyridine-2 -On-5-boronic acid pinacol ester (0.398 g; 1.7 mmol) was reacted and purified as in Example 6. The title compound was isolated as dihydrochloride as 100 mg (18%) as a white solid.
LC-MS (electrospray): m / z: 312 (M + 1), Rt = 0.57 min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.05 (d, 1H), 8.8 (d, d, 1H), 8.4 (d, 1H), 8.1 (d, 1H), 7.95 (d, d, 1H ), 6.72 (d, 1H), 3.7 (s, 3H), 3.4-3.6 (m, 4H), 3.3-3.35 (m, 2H), 2.3-2.4 (m, 4H), 1.4 (d, 6H).

Example 11 (General production method A)
[4- (1′-Isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) phenyl] pyrrolidin-1-yl-methanone Dihydrochloride:

5-Bromo-1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (400 mg; 1.4 mmol) and N-pyrrolodinyl-1- Carbonylphenyl-4-boronic acid (0.327 g; 1.7 mmol) was reacted and purified in the same manner as Example 6. 300 mg (47%) of white crystals were isolated as the dihydrochloride of the title compound.
LC-MS (electrospray): m / z: 378 (M + 1), Rt = 0.93 min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.1 (s, 1H), 8.9 (d, d, 1H), 8.15 (d, 1H), 7.9 (d, 2H), 7.7 (d, 2H), 3.45-3.8 (m, 8H), 3.3-3.45 (m, 2H), 2.5-2.45 (m, 4H), 1.85-2.05 (m, 4H), 1.5 (d, 6H).

５-ブロモ-１'-イソプロピル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(４００ｍｇ；１.４ｍｍｏｌ)及び４-(１-ピペリジニルスルホニル)フェニルボロン酸(０.３２７ｇ；１.７ｍｍｏｌ)を、実施例６と同じ様式で反応させ、そして精製した。標題の化合物を、ジヒドロクロリド３００ｍｇ(４７％)を白色固体として単離した。
LC-MS (エレクトロスプレー): m/z: 428 (M+1), Rt= 1.19分
¹H NMR(300 MHz,MeOH-D4) δ: 9.16 (d, J=2.02 Hz, 1H), 8.88 (dd, J=8.59, 2.02 Hz, 1H), 8.12 (d, J=8.08 Hz, 1H), 8.05 (d, 2H), 7.94 (d, J=8.08 Hz, 2H), 3.46 - 3.73 (m, 6H), 3.28 - 3.38 (m, 2H), 2.99 - 3.06 (m, 4H), 2.28 - 2.47 (m, 4H), 1.59 - 1.68 (m, 4H), 1.41 - 1.50 (m,8H). Example 12 (General production method A)
1′-isopropyl-5- [4- (piperidine-1-sulfonyl) phenyl] -1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl, dihydrochloride :

5-Bromo-1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (400 mg; 1.4 mmol) and 4- (1-pi Peridinylsulfonyl) phenylboronic acid (0.327 g; 1.7 mmol) was reacted and purified in the same manner as Example 6. The title compound was isolated as a white solid, 300 mg (47%) of dihydrochloride.
LC-MS (electrospray): m / z: 428 (M + 1), Rt = 1.19 min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.16 (d, J = 2.02 Hz, 1H), 8.88 (dd, J = 8.59, 2.02 Hz, 1H), 8.12 (d, J = 8.08 Hz, 1H) , 8.05 (d, 2H), 7.94 (d, J = 8.08 Hz, 2H), 3.46-3.73 (m, 6H), 3.28-3.38 (m, 2H), 2.99-3.06 (m, 4H), 2.28-2.47 (m, 4H), 1.59-1.68 (m, 4H), 1.41-1.50 (m, 8H).

５-ブロモ-１'-イソプロピル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(０.５０Ｏｇ；２ｍｍｏｌ)及び４-エタンスルホニルフェニルボロン酸(０.３７７ｇ；２ｍｍｏｌ)を、実施例６と同じ様式で反応させ、そして精製した。標題の化合物を、二塩酸塩、４１３ｇ(４６％)の白色結晶として単離した。
LC-MS(エレクトロスプレー): m/z: 377 (M+1), Rt= 0.947分
¹H NMR (300 MHz, MeOH-D4) δ: 8.9(d, １Ｈ), 8.55(d, １Ｈ), 8.48(d, 2H), 8.15(d, 2H), 3.6- 3.75(m, 4H), 3.25-3.4(m, 4H), 2.45(m, 4H), 1.46(d, 6H), 1.25(t, 3H). Example 13 (General production method A)
3- (4-ethanesulfonylphenyl) -6- (1-isopropylpiperidin-4-yl) pyridazine, dihydrochloride:

5-Bromo-1′-isopropyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (0.5Og; 2 mmol) and 4-ethanesulfonylphenylboron The acid (0.377 g; 2 mmol) was reacted and purified in the same manner as Example 6. The title compound was isolated as the dihydrochloride salt, 413 g (46%) of white crystals.
LC-MS (electrospray): m / z: 377 (M + 1), Rt = 0.947 min
¹ H NMR (300 MHz, MeOH-D4) δ: 8.9 (d, 1H), 8.55 (d, 1H), 8.48 (d, 2H), 8.15 (d, 2H), 3.6-3.75 (m, 4H), 3.25-3.4 (m, 4H), 2.45 (m, 4H), 1.46 (d, 6H), 1.25 (t, 3H).

ステップ１：
５-ブロモ-１'-シクロブチル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル：

５-ブロモ-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(６.４ｇ、１８.０２ｍｍｏｌ)を、２％酢酸を含むＭｅＯＨ(４０ｍｌ)に溶解した。プロパノン(８ｍＬ、１１３ｍｍｏｌ)及びＮａ(ＣＮ)ＢＨ₃(３.６ｇ,５７ｍｍｏｌ)を加えた。反応混合液を室温で一晩撹拌した。反応混合液に１ＮのＨＣｌを加え、吸引下でろ過し、そして濃縮した。化合物を水中に溶解し、そしてｐＨを１２に調節し、次にＤＣＭ(３×２００ｍｌ)で抽出した。粗製生成物を、１Ｎ・ＨＣｌで１時間処理し、そしてジエチルエーテルで抽出して不純物を取り除いた。水相のｐＨをｐＨ＝５.８〜９に調節した。酢酸エチルで抽出し(３×１００ｍｌ)有機相をＮａ₂ＣＯ₃で乾燥し、ろ過し、そして蒸発させて、４.６ｇ(８６％)の白色結晶を与えた。
LC-MS(エレクトロスプレー):m/z:295 (M+1), Rt= 0.95分
Mp= 122.3-124.3℃
¹H NMR(300MHz, CDCl₃) δ: 8.6(d, 1H), 7.9(d,d, 1H), 7.5(s, 1H), 7.1 (d, 1H), 3.2(m, 2H), 2.62-2.79(m, 2H), 2.0-2.1 (m, 2H), 1.6-1.97(m, 10H). Example 14 (General production method A)
[4- (1'-cyclobutyl-1 ', 2', 3 ', 4', 5 ', 6'-hexahydro- [2,4'] bipyridinyl-5-yl) phenyl]-(4-methylpiperazine- 1-yl) methanone, trihydrochloride:

Step 1 :
5-Bromo-1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl:

5-Bromo-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (6.4 g, 18.02 mmol) was added to 2% acetic acid in MeOH (40 ml ). Propanone (8 mL, 113 mmol) and Na (CN) BH ₃ (3.6 g, 57 mmol) were added. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was added 1N HCl, filtered under suction and concentrated. The compound was dissolved in water and the pH was adjusted to 12, then extracted with DCM (3 × 200 ml). The crude product was treated with 1N HCl for 1 hour and extracted with diethyl ether to remove impurities. The pH of the aqueous phase was adjusted to pH = 5.8-9. Extracted with ethyl acetate (3 × 100 ml) and the organic phase was dried over Na ₂ CO ₃ , filtered and evaporated to give 4.6 g (86%) of white crystals.
LC-MS (electrospray): m / z: 295 (M + 1), Rt = 0.95 min
Mp = 122.3-124.3 ℃
¹ H NMR (300MHz, CDCl ₃ ) δ: 8.6 (d, 1H), 7.9 (d, d, 1H), 7.5 (s, 1H), 7.1 (d, 1H), 3.2 (m, 2H), 2.62- 2.79 (m, 2H), 2.0-2.1 (m, 2H), 1.6-1.97 (m, 10H).

Step 2 :
5-Bromo-1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (0.8 g; 2.7 mmol), 4-(( 4-methylpiperazin-1-yl) -4- (4,4,5,5-tetramethyl- [1,3,2] dioxoborolan-2-yl) phenyl) methanone (1.07 g; 3.3 mmol) and Bis (triphenylphosphine) palladium (II) chloride (100 mg, 0.14 mmol) was mixed in acetonitrile (7 ml) and 1M Na ₂ CO ₃ (7 ml) in a 20 ml electromagnetic vial under N ₂ atmosphere. The reaction mixture was heated at 85 ° C. for 1500 seconds. The aqueous phase was removed, 1N HCl (3 ml) was added to the acetonitrile phase, and the solution was purified by preparative HPLC (Method B). The product was isolated as a TFA salt. After dissolving in MeOH and adding 1 N HCl (5 ml) and evaporating under suction, the title compound was obtained as the trihydrochloride salt. Yield: 1 g (67%).
LC-MS (electrospray): m / z: 419.8 (M + 1), Rt = 1.05 min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.16 (d, J = 2.02 Hz, 1H) 8.94 (dd, J = 8.59, 2.02 Hz, 1H) 8.18 (d, J = 8.59 Hz, 1H) 7.98 ( d, J = 8.08 Hz, 2H) 7.73 (d, J = 8.08 Hz, 2H) 3.51-3.82 (m, 8H) 3.30-3.35 (m, 2H) 3.20-3.29 (m, 2H) 3.04-3.15 (m, 2H) 2.97 (s, 3H) 2.24-2.53 (m, 8H) 1.81-1.99 (m, 2H).

５-ブロモ-１'-シクロブチル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(０.８ｇ；２.７ｍｍｏｌ)、Ｎ,Ｎ-ジ-メチルベンズアミド-４-ボロン酸(０.６２７ｇ；３.３ｍｍｏｌ)及びビス(トリフェニルホスフィン)パラジウム-(II)クロリド(１００ｍｇ、０.１４ｍｍｏｌ)を、２０ｍｌの電磁波バイアル中で、窒素雰囲気下でアセトニトリル(８ｍｌ)と１Ｍ・Ｎａ₂ＣＯ₃(８ｍｌ)と混合した。反応混合液を８５℃で１５００秒間加熱した。水相を取り除き、アセトニトリル相に１Ｎ・ＨＣｌ(３ｍｌ)を加え、そして溶液を調製的ＨＰＬＣ(方法Ｂ)で精製した。生成物をＴＦＡ塩として単離した。ＭｅＯＨ中に再溶解し、そして１Ｎ・ＨＣｌ(５ｍｌ)を加えて、吸引下で蒸発後にジヒドロクロリド塩として標題の化合物を与えた。収率：５００ｇ(４２％)白色結晶。
LC-MS(エレクトロスプレー): m/z: 364.6 (M+1), Rt= 0.767分
¹H NMR (300 MHz, MeOH-D4) δ: 9.14 (d, J=2.02 Hz, 1H) 8.92 (dd, J=8.59, 2.02Hz, 1H) 8.15 (d, J=8.59 Hz, 1H) 7.93 (d, J=8.59 Hz, 2H) 7.65 (d, J=8.08 Hz, 2H) 3.64 - 3.82 (m, 3H) 3.48 - 3.60 (m, 1H) 3.14 (s, 3H) 3.06 - 3.12 (m, 2H) 3.04 (s, 3H) 2.23 - 2.51 (m, 8H) 1.80 - 1.99 (m, 2H). Example 15 (General production method A)
4- (1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) -N, N-dimethylbenzamide, dihydrochloride :

5-bromo-1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (0.8 g; 2.7 mmol), N, N— Di-methylbenzamide-4-boronic acid (0.627 g; 3.3 mmol) and bis (triphenylphosphine) palladium- (II) chloride (100 mg, 0.14 mmol) were placed in a 20 ml electromagnetic wave vial under nitrogen atmosphere. Mixed with acetonitrile (8 ml) and 1M Na ₂ CO ₃ (8 ml). The reaction mixture was heated at 85 ° C. for 1500 seconds. The aqueous phase was removed, 1N HCl (3 ml) was added to the acetonitrile phase, and the solution was purified by preparative HPLC (Method B). The product was isolated as a TFA salt. Redissolved in MeOH and 1N HCl (5 ml) was added to give the title compound as the dihydrochloride salt after evaporation under suction. Yield: 500 g (42%) white crystals.
LC-MS (electrospray): m / z: 364.6 (M + 1), Rt = 0.767 min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.14 (d, J = 2.02 Hz, 1H) 8.92 (dd, J = 8.59, 2.02Hz, 1H) 8.15 (d, J = 8.59 Hz, 1H) 7.93 ( d, J = 8.59 Hz, 2H) 7.65 (d, J = 8.08 Hz, 2H) 3.64-3.82 (m, 3H) 3.48-3.60 (m, 1H) 3.14 (s, 3H) 3.06-3.12 (m, 2H) 3.04 (s, 3H) 2.23-2.51 (m, 8H) 1.80-1.99 (m, 2H).

５-ブロモ-１'-シクロブチル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(０.７ｇ；２.３７ｍｍｏｌ)、Ｎ,Ｎ-ジエチルベンズアミド-４-ボロン酸(０.５７７ｇ；２.６１ｍｍｏｌ)を混合し、そして実施例１５と全く同じ様式で混合し、そして反応させ、そして精製した。
収率：９００ｍｇ(８１％)標題の化合物の二塩酸塩の白色結晶であった。
LC-MS (エレクトロスプレー): m/z: 392.6 (M+1), Rt= 0.881分
¹H NMR (300 MHz, MeOH-D4) δ: 9.15 (d, J=2.02 Hz, 1H) 8.94 (dd, J=8.59, 2.02 Hz, 1H)8.17 (d, J=8.08 Hz, 1H) 7.94 (d, J=8.59 Hz, 2H) 7.60 (d, J=8.08 Hz, 2H) 3.64 - 3.88 (m, 3H) 3.46 - 3.63 (m, 3H) 3.27 - 3.39 (m, 2H) 2.98 - 3.16 (m, 2H) 2.18 - 2.54 (m, 8H) 1.72 - 2.03 (m, 2H) 1.28 (t, J=7.07 Hz, 3H) 1.15 (t, J=6.82 Hz, 3H). Example 16 (General production method A)
4- (1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) -N, N-diethylbenzamide, dihydrochloride :

5-bromo-1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (0.7 g; 2.37 mmol), N, N— Diethylbenzamide-4-boronic acid (0.577 g; 2.61 mmol) was mixed and mixed and reacted and purified in exactly the same manner as Example 15.
Yield: 900 mg (81%) white crystals of the dihydrochloride salt of the title compound.
LC-MS (electrospray): m / z: 392.6 (M + 1), Rt = 0.881 min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.15 (d, J = 2.02 Hz, 1H) 8.94 (dd, J = 8.59, 2.02 Hz, 1H) 8.17 (d, J = 8.08 Hz, 1H) 7.94 ( d, J = 8.59 Hz, 2H) 7.60 (d, J = 8.08 Hz, 2H) 3.64-3.88 (m, 3H) 3.46-3.63 (m, 3H) 3.27-3.39 (m, 2H) 2.98-3.16 (m, 2H) 2.18-2.54 (m, 8H) 1.72-2.03 (m, 2H) 1.28 (t, J = 7.07 Hz, 3H) 1.15 (t, J = 6.82 Hz, 3H).

５-ブロモ-１'-シクロブチル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(０.７３ｇ；２.５ｍｍｏｌ)、Ｎ-ピロロジニル-１-カルボニルフェニル-４-ボロン酸(０.６５ｇ；３.０ｍｍｏｌ)を、実施例１５と全く同じ様式で混合し、そして反応させ、そして精製した。
収率:７１０ｍｇ(６２％)、標題の化合物のジヒドロクロリドの白色固体
LC-MS(エレクトロスプレー):m/z:390.6 (M+1), Rt= 0.937分
¹H NMR (300 MHz, MeOH-D4) δ: 9.15(s, 1H), 9.89(d,d, 1H), 8.18(d, 2H), 7.95(d, 2H), 7.75(d,2H), 3.5-3.8(m, 6H), 3.1 (d, t, 2H), 2.2-2.5(m, 8H), 1.8-2.1 (m, 8H). Example 17 (General production method A)
[4- (1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) phenyl] pyrrolidin-1-yl-methanone , Dihydrochloride:

5-Bromo-1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (0.73 g; 2.5 mmol), N-pyrrolodinyl- 1-carbonylphenyl-4-boronic acid (0.65 g; 3.0 mmol) was mixed and reacted and purified in exactly the same manner as Example 15.
Yield: 710 mg (62%), white solid of the title compound dihydrochloride
LC-MS (electrospray): m / z: 390.6 (M + 1), Rt = 0.937 min
¹ H NMR (300 MHz, MeOH-D4) δ: 9.15 (s, 1H), 9.89 (d, d, 1H), 8.18 (d, 2H), 7.95 (d, 2H), 7.75 (d, 2H), 3.5-3.8 (m, 6H), 3.1 (d, t, 2H), 2.2-2.5 (m, 8H), 1.8-2.1 (m, 8H).

ステップ１：

６-(１-イソプロピルピペリジン-４-イル)ピリダジン-３-オン：
Wermuthら、J. Med. Chem. 1987, 30 (2), 246と同様に、ヒドラジン水和物(１０ｍｌ)を、４-(１-イソプロピルピペリジン-４-イル)-２-モルホリン-４-イル-４-オキソ-酪酸(９９.９ｇ、０.２５ｍｏｌ)を入れた２-ブタノール(５００ｍＬ)の溶液に加えた。反応混合液を室温で１時間撹拌し、続いて一晩還流した。室温に冷却後、溶媒を減圧下で蒸発させた。残渣をフラッシュカラムクロマトグラフィー(ＳｉＯ₂、３％メタノールの次に５％及び７％のメタノールを含むジクロロメタン)により精製した。所望の生成物を含む画分を蒸発させて、黄色固体を生成した。当該固体をそのまま用いた。収率１６.０ｇ＝３つの反応ステップにわたって２９％であった。
LC-MS (エレクトロスプレー): m/z: 222 (M+1); Rt = 0.26分
¹H NMR (300 MHz, CDCl₃) δ: 12.6 (v.br.s, 1 H, 7.23 (d, J = 9.6 Hz, 1H), 6.92 (d, J = 9.60 Hz, 1H), 3.02 (m, 2H), 2.84 (septet, J = 6.57 Hz, 1H), 2.53 (m, 1H), 2.26 (dt, J = 11.12, 3.54 Hz, 2H), 1.85 (m, 4H), 1.10 (d, J = 6.57 Hz, 6H). Example 18 (General production method A)
4- [6- (1-Isopropylpiperidin-4-yl) pyridazin-3-yl] -N, N-dimethylbenzenesulfonamide, dihydrochloride:

Step 1 :

6- (1-Isopropylpiperidin-4-yl) pyridazin-3-one:
Similar to Wermuth et al., J. Med. Chem. 1987, 30 (2), 246, hydrazine hydrate (10 ml) was treated with 4- (1-isopropylpiperidin-4-yl) -2-morpholin-4-yl. To a solution of 2-butanol (500 mL) containing -4-oxo-butyric acid (99.9 g, 0.25 mol) was added. The reaction mixture was stirred at room temperature for 1 hour and subsequently refluxed overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane, including: 5% and 7% methanol SiO _2, 3% methanol). Fractions containing the desired product were evaporated to yield a yellow solid. The solid was used as is. Yield 16.0 g = 29% over 3 reaction steps.
LC-MS (electrospray): m / z: 222 (M + 1); Rt = 0.26 min
¹ H NMR (300 MHz, CDCl ₃ ) δ: 12.6 (v.br.s, 1 H, 7.23 (d, J = 9.6 Hz, 1H), 6.92 (d, J = 9.60 Hz, 1H), 3.02 (m , 2H), 2.84 (septet, J = 6.57 Hz, 1H), 2.53 (m, 1H), 2.26 (dt, J = 11.12, 3.54 Hz, 2H), 1.85 (m, 4H), 1.10 (d, J = 6.57 Hz, 6H).

６-(１-イソプロピルピペリジン-４-イル)ピリダジン-３-オン(５.７６ｇ,２６ｍｍｏｌ)を、ＰＯＣｌ₃(５ＯｍＬ)に加え、そして反応混合液を６０℃で２時間加熱した。過剰量のＰＯＣｌ₃を吸引下で蒸発させ、そして発熱反応の下でエタノール(９６％)を加えた。反応混合液を冷却し、そして沈殿を得た。吸引下で生成物をろ別し、そして６.３４ｇ(８８％)の白色結晶を単離した。
LC-MS(エレクトロスプレー): m/z: 240(M+1); Rt = 0.53分
¹H NMR (300 MHz, CDCl₃) δ: 10.50 (br.s, 1H), 7.95 (d, 1H) 7.80 (d, 1H), 3.51 (m, 3H), 3.31 (m, 1H), 3.18 (m, 2H), 2.30 (m, 2H), 2.18 (m, 2H), 1.35 (d, 6H). Step 2 :
3-Chloro-6- (1-isopropylpiperidin-4-yl) pyridazine, hydrochloride:

6- (1-Isopropylpiperidin-4-yl) pyridazin-3-one (5.76 g, 26 mmol) was added to POCl ₃ (5 OmL) and the reaction mixture was heated at 60 ° C. for 2 h. Excess POCl ₃ was evaporated under suction and ethanol (96%) was added under an exothermic reaction. The reaction mixture was cooled and a precipitate was obtained. The product was filtered off under suction and 6.34 g (88%) of white crystals were isolated.
LC-MS (electrospray): m / z: 240 (M + 1); Rt = 0.53 min
¹ H NMR (300 MHz, CDCl ₃ ) δ: 10.50 (br.s, 1H), 7.95 (d, 1H) 7.80 (d, 1H), 3.51 (m, 3H), 3.31 (m, 1H), 3.18 ( m, 2H), 2.30 (m, 2H), 2.18 (m, 2H), 1.35 (d, 6H).

Step 3 :
3-chloro-6- (1-isopropylpiperidin-4-yl) pyridazine, hydrochloride (0.5 g, 1.6 mmol), N, N-di-methyl-4-boronobenzenesulfonamide (0.4 g, 1.76 mmol) and PdCl ₂ (PPh ₃ ) ₂ (0.056 g, 0.08 mmol) were mixed with 1 N Na ₂ CO ₃ (3 mL) and acetonitrile (2 mL) in a 5 ml MW vial. The reaction mixture was heated in a microwave at 130 ° C. for 500 seconds. Water (5 ml) was added to the reaction mixture and extracted with DCM (3 × 10 ml). The DCM phase was evaporated under suction, redissolved in acetonitrile and a few drops of TFA and extracted with DCM (3 × 10 ml). The TFA salt was purified by preparative HPLC (Method B). The title compound was isolated as a TFA salt. This salt was dissolved in MeOH (3 ml) and diethyl ether containing HCl was added. Evaporation gave 438 mg (59%) of the dihydrochloride as slightly brown crystals.
LC-MS (electrospray): m / z: 390 (M + 1); Rt = 1.04 min
^{1 HNMR (400 MHz, MeOH-} D4) δ: 8.8 (d, 1H), 8.45 (d, 1H), 8.45 (d, 2H), 8.02 (d, 2H), 3.55- 3.75 (m, 4H), 3.35 (m, 2H), 2.25 (s, 6H), 2.3-2.5 (m, 4H), 1.45 (d, 6H).

３-クロロ-６-(１-イソプロピルピペリジン-４-イル)ピリダジン,ヒドロクロリド(０.５ｇ,１.６ｍｍｏｌ)と２-メチルピリジンボロン酸(０.２４１ｇ、１.７６ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を、三塩酸塩の白色結晶として単離した。収率１６４ｍｇ(２５％)。
LC-MS (エレクトロスプレー): m/z: 298 (M+1); Rt = 0.544 分
¹H NMR (400 MHz, MeOH-D4) δ: 8.88(d,d, 1H), 8.75(s, 1H), 8.68(d, 2H), 8.12(d, 1H), 3.45- 3.7(m, 4H), 3.3(m, 2H), 2.9(s, 3H), 2.35(m, 3H), 1.45(d, 6H). Example 19 (General production method A)
3- (1-Isopropylpiperidin-4-yl) -6- (2-methylpyridin-4-yl) pyridazine, trihydrochloride:

3-Chloro-6- (1-isopropylpiperidin-4-yl) pyridazine, hydrochloride (0.5 g, 1.6 mmol) and 2-methylpyridineboronic acid (0.241 g, 1.76 mmol) were mixed with the catalyst. And reacted in the same manner as Example 18. The title compound was isolated as white crystals of the trihydrochloride salt. Yield 164 mg (25%).
LC-MS (electrospray): m / z: 298 (M + 1); Rt = 0.544 min
¹ H NMR (400 MHz, MeOH-D4) δ: 8.88 (d, d, 1H), 8.75 (s, 1H), 8.68 (d, 2H), 8.12 (d, 1H), 3.45- 3.7 (m, 4H ), 3.3 (m, 2H), 2.9 (s, 3H), 2.35 (m, 3H), 1.45 (d, 6H).

３-クロロ-６-(１-イソプロピルピペリジン-４-イル)ピリダジン,ヒドロクロリド(０.４２２ｇ,１.３５ｍｍｏｌ)及びＮ-メチルピリジン-２-オン-５-ボロン酸(０.３４９ｇ,１.４８５ｍｍｏｌ)を、実施例１８に記載されるのと同じ様式で触媒と混合し、そして反応させた。標題の化合物を二塩酸塩の白色結晶として単離した：収率：３００ｍｇ(５８％)。
LC-MS (エレクトロスプレー): m/z: 314 (M+1); Rt = 0.708 分
¹HNMR (400 MHz, MeOH-D4) δ: 8.75(d, １Ｈ), 8.7(d, １Ｈ), 8.4(d, １Ｈ), 8.2(d,d, １Ｈ), 3.7(s, 3H), 3.45-3.65(m, 5H), 3.3(m, １Ｈ), 2.35(m, 4H), 1.45(d, 6H). Example 20 (General production method A)
5- [6- (1-Isopropylpiperidin-4-yl) pyridazin-3-yl] -1-methyl-1H-pyridin-2-one, dihydrochloride:

3-Chloro-6- (1-isopropylpiperidin-4-yl) pyridazine, hydrochloride (0.422 g, 1.35 mmol) and N-methylpyridin-2-one-5-boronic acid (0.349 g, 1. 485 mmol) was mixed and reacted with the catalyst in the same manner as described in Example 18. The title compound was isolated as white crystals of the dihydrochloride salt: yield: 300 mg (58%).
LC-MS (electrospray): m / z: 314 (M + 1); Rt = 0.708 min
¹ HNMR (400 MHz, MeOH-D4) δ: 8.75 (d, 1H), 8.7 (d, 1H), 8.4 (d, 1H), 8.2 (d, d, 1H), 3.7 (s, 3H), 3.45 -3.65 (m, 5H), 3.3 (m, 1H), 2.35 (m, 4H), 1.45 (d, 6H).

５-ブロモ-１'-シクロブチル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(０.３８７ｇ；１.３１２ｍｍｏｌ)及び４-エタンスルホニルフェニルボロン酸(０.３３７ｇ；１.５７ｍｍｏｌ)を、実施例１８と同じ様式で触媒と混合し、そして反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：２１８ｍｇ(３６％)。
LC-MS (エレクトロスプレー): m/z: 385 (M+1); Rt = 0.98分
¹H NMR (400 MHz, MeOH-D4) δ: 9.2(s, 1H), 8.89(d,d, 1H), 8.1 (m, 5H), 3.65-3.75(m, 3H), 3.5(m, 1H), 3.3(m, 2H), 3.05(d,t, 2H), 2.1-2.45(m, 8H), 1.9(m, 2H), 1.25(t, 3H). Example 21 (General production method A)
1′-cyclobutyl-5- (4-ethanesulfonylphenyl) -1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl, dihydrochloride:

5-Bromo-1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (0.387 g; 1.312 mmol) and 4-ethanesulfonyl Phenylboronic acid (0.337 g; 1.57 mmol) was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 218 mg (36%).
LC-MS (electrospray): m / z: 385 (M + 1); Rt = 0.98 min
¹ H NMR (400 MHz, MeOH-D4) δ: 9.2 (s, 1H), 8.89 (d, d, 1H), 8.1 (m, 5H), 3.65-3.75 (m, 3H), 3.5 (m, 1H ), 3.3 (m, 2H), 3.05 (d, t, 2H), 2.1-2.45 (m, 8H), 1.9 (m, 2H), 1.25 (t, 3H).

５-ブロモ-１'-シクロブチル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(０.３８７ｇ；１.３１２ｍｍｏｌ)及びＮ,Ｎ-ジメチル-４-ボロノベンゼンスルホンアミド(０.３６１ｇ；１.５７ｍｍｏｌ)を、実施例１８と同じ様式で触媒と混合し、そして反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：３１３ｍｇ(５０％)
LC-MS (エレクトロスプレー): m/z: 400 (M+1); Rt = 1.07分
¹H NMR (400 MHz, MeOH-D4) δ: 9.15(s, 1H), 8.9(d, 1H), 7.9-8.12(m, 5H), 3.65-3.78(m, 3H), 3.05(m, 2H), 2.7(s, 6H), 2.2-2.45(m, 8H), 1.3-2.0(m, 2H). Example 22 (General production method A)
4- (1'-cyclobutyl-1 ', 2', 3 ', 4', 5 ', 6'-hexahydro- [2,4'] bipyridinyl-5-yl) -N, N-dimethylbenzene-sulfonamide Dihydrochloride:

5-Bromo-1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (0.387 g; 1.312 mmol) and N, N— Dimethyl-4-boronobenzenesulfonamide (0.361 g; 1.57 mmol) was mixed and reacted with the catalyst in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 313 mg (50%)
LC-MS (electrospray): m / z: 400 (M + 1); Rt = 1.07 min
¹ H NMR (400 MHz, MeOH-D4) δ: 9.15 (s, 1H), 8.9 (d, 1H), 7.9-8.12 (m, 5H), 3.65-3.78 (m, 3H), 3.05 (m, 2H ), 2.7 (s, 6H), 2.2-2.45 (m, 8H), 1.3-2.0 (m, 2H).

５-ブロモ-１'-シクロブチル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル(０.３８７ｇ；１.３１２ｍｍｏｌ)及び２-メチル-４-ピリジンボロン酸(０.２１５ｇ；１.５７ｍｍｏｌ)を、実施例１８と同じ様式で触媒と混合し、そして反応させた。標題の化合物を三塩酸塩の白色結晶として単離した。収率：３１３ｍｇ(５０％)
LC-MS (エレクトロスプレー): m/z: 308.6 (M+1); Rt = 0.67 分
¹H NMR (400 MHz, MeOH-D4) δ: 9.3(s, 1H), 8.8(d, 1H), 8.78(d,d, 1H), 8.45(s, 1H), 8.3(d, 1H), 8.8(d, 1H), 3.4-3.8(m, 3H), 3.4(m, 1H), 3.05(d,t, 2H), 2.9(s, 3H), 2.2-2.(m, 8H), 1.8- 1.95(m, 2H). Example 23 (General production method A)
1-cyclobutyl-2 ″ -methyl-1,2,3,4,5,6-hexahydro- [4,2 ′; 5 ′, 4 ″] terpyridine, trihydrochloride:

5-Bromo-1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl (0.387 g; 1.312 mmol) and 2-methyl- 4-Pyridineboronic acid (0.215 g; 1.57 mmol) was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the trihydrochloride salt. Yield: 313 mg (50%)
LC-MS (electrospray): m / z: 308.6 (M + 1); Rt = 0.67 min
¹ H NMR (400 MHz, MeOH-D4) δ: 9.3 (s, 1H), 8.8 (d, 1H), 8.78 (d, d, 1H), 8.45 (s, 1H), 8.3 (d, 1H), 8.8 (d, 1H), 3.4-3.8 (m, 3H), 3.4 (m, 1H), 3.05 (d, t, 2H), 2.9 (s, 3H), 2.2-2. (M, 8H), 1.8 -1.95 (m, 2H).

１-シクロブチル-２''-メチル-１,２,３,４,５,６-ヘキサヒドロ-［４,２'；５',４''］ターピリジン(０.４０ｇ、０.８６ｍｍｏｌ)を乾燥ＴＨＦ(１５ｍＬ)中に溶解し、ガスが激しく発生するため、５ｅｑ.２ＮのＬｉＡＩＨ₄を含むＴＨＦをかなりゆっくりシリンジを通して窒素雰囲気下で加えた。反応混合液は橙色に変色した。反応混合液を室温で３時間撹拌した。水と１０％Ｋ₂ＣＯ₃を含む水(１：３)を注意深く加えた。反応混合液をろ過し、そしてろ過ケーキを、ＴＨＦで洗浄した(３×１０ｍｌ)。ＴＨＦ相を吸引下で蒸発させ、そしてＭｅＯＨ中に溶解し、１Ｎ・ＨＣｌ(１ｍｌ)を加え、そして調製的ＨＰＬＣ(方法Ｂ)で精製した。蒸発させることによりＴＦＡ塩を得て、そしてＨＣｌを含むジエチルエーテルを加えて、吸引下で蒸発させることにより標題の化合物を三塩酸塩として得た。収率３５ｍｇ、(１０％)白色結晶。
LC-MS (エレクトロスプレー): m/z: 378 (M+1); Rt = 0.44 分
¹H NMR (400 MHz, MeOH-D4) δ: 9.10 (s, １Ｈ), 8.79 (d, J=7.58 Hz, １Ｈ), 8.05 (d, J=8.08 Hz, １Ｈ), 7.95 (d, J=7.58 Hz, 2H), 7.77 (d, J=7.58 Hz, 2H), 4.46 (s, 2H), 3.65 - 3.79 (m, 3H), 3.40 - 3.52 (m, １Ｈ), 3.21 - 3.29 (m, 4H), 3.06 (t, J=12.13 Hz, 2H), 2.24 - 2.45 (m, 8H), 1.83 - 1.99 (m, 2H), 1.38 (t, J=7.07 Hz, 6H). Example 24 (General production method A)
[4- (1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) benzyl] pipetylamine, trihydrochloride:

1-cyclobutyl-2 ″ -methyl-1,2,3,4,5,6-hexahydro- [4,2 ′; 5 ′, 4 ″] terpyridine (0.40 g, 0.86 mmol) was dried in THF Since it dissolved in (15 mL) and gas evolved vigorously, THF containing ₅ eq. 2 N LiAIH ₄ was added fairly slowly through a syringe under a nitrogen atmosphere. The reaction mixture turned orange. The reaction mixture was stirred at room temperature for 3 hours. Water and water containing 10% K ₂ CO ₃ (1: 3) were carefully added. The reaction mixture was filtered and the filter cake was washed with THF (3 × 10 ml). The THF phase was evaporated under suction and dissolved in MeOH, 1N HCl (1 ml) was added and purified by preparative HPLC (Method B). Evaporation gave the TFA salt and the addition of diethyl ether containing HCl and evaporation under suction gave the title compound as the trihydrochloride salt. Yield 35 mg, (10%) white crystals.
LC-MS (electrospray): m / z: 378 (M + 1); Rt = 0.44 min
¹ H NMR (400 MHz, MeOH-D4) δ: 9.10 (s, 1H), 8.79 (d, J = 7.58 Hz, 1H), 8.05 (d, J = 8.08 Hz, 1H), 7.95 (d, J = 7.58 Hz, 2H), 7.77 (d, J = 7.58 Hz, 2H), 4.46 (s, 2H), 3.65-3.79 (m, 3H), 3.40-3.52 (m, 1H), 3.21-3.29 (m, 4H ), 3.06 (t, J = 12.13 Hz, 2H), 2.24-2.45 (m, 8H), 1.83-1.99 (m, 2H), 1.38 (t, J = 7.07 Hz, 6H).

［４-(１'-シクロブチル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル-５-イル)フェニル］ピロリジン-１-イル-メタノン,ジヒドロクロリド(０.３５ｇ,０.７５７ｍｍｏｌ)を、実施例２４に記載されるのと同じ様式で反応させ、そして精製した。
収率：５０ｍｇ(１６％)三塩化塩の白色結晶
LC-MS (エレクトロスプレー): m/z: 376 (M+1); Rt = 0.99 分
¹H NMR (400 MHz, MeOH-D4) δ: 9.11 (s, 1H), 8.83(d, 1H), 8.08(d, 1H), 7.95(d, 2H), 7.78(d, 2H), 4.49(s, 2H), 3.49-3.82(m, 6h), 3.17-3.28(m, 2H), 3.06(t, 2H), 2.17-2.48(m, 10H), 2.01- 2.09(m, 2H), 1.83-1.98(m, 2H). Example 25 (General production method A)
1'-cyclobutyl-5- (4-pyrrolidin-1-ylmethylphenyl) -1 ', 2', 3 ', 4', 5 ', 6'-hexahydro- [2,4'] bipyridinyl, trihydrochloride :

[4- (1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) phenyl] pyrrolidin-1-yl-methanone , Dihydrochloride (0.35 g, 0.757 mmol) was reacted and purified in the same manner as described in Example 24.
Yield: 50 mg (16%) white crystals of trichloride
LC-MS (electrospray): m / z: 376 (M + 1); Rt = 0.99 min
¹ H NMR (400 MHz, MeOH-D4) δ: 9.11 (s, 1H), 8.83 (d, 1H), 8.08 (d, 1H), 7.95 (d, 2H), 7.78 (d, 2H), 4.49 ( s, 2H), 3.49-3.82 (m, 6h), 3.17-3.28 (m, 2H), 3.06 (t, 2H), 2.17-2.48 (m, 10H), 2.01- 2.09 (m, 2H), 1.83- 1.98 (m, 2H).

４-(１'-シクロブチル-１',２',３',４',５',６'-ヘキサヒドロ-［２,４'］ビピリジニル-５-イル)-Ｎ,Ｎ-ジメチルベンズアミド,ジヒドロクロリド(０.３３ｇ,０.６８７ｍｍｏｌ)を、実施例２４に記載されるのと同じ様式で反応させ、そして精製した。
収率：１４ｍｇ(４％)三塩酸塩の白色結晶
LC-MS (エレクトロスプレー): m/z: 359 (M+1); Rt = 0.65 分
¹H NMR (400 MHz, MeOH-D4) δ: 9.15(s, 1H), 8.92(d, 1H), 8.16(d, 1H), 7.98(d, 2H), 7.79(d, 2H), 4.45(s, 2H), 3.46-3.85(m, 4H), 3.09(t, 2H), 2.91 (s, 6H), 2.22-2.54(m, 8H), 1.73-2.06(m, 2H). Example 26 (General production method A)
[4- (1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) benzyl] dimethylamine, trihydrochloride:

4- (1′-cyclobutyl-1 ′, 2 ′, 3 ′, 4 ′, 5 ′, 6′-hexahydro- [2,4 ′] bipyridinyl-5-yl) -N, N-dimethylbenzamide, dihydrochloride (0.33 g, 0.687 mmol) was reacted and purified in the same manner as described in Example 24.
Yield: 14 mg (4%) trihydrochloride white crystals
LC-MS (electrospray): m / z: 359 (M + 1); Rt = 0.65 min
¹ H NMR (400 MHz, MeOH-D4) δ: 9.15 (s, 1H), 8.92 (d, 1H), 8.16 (d, 1H), 7.98 (d, 2H), 7.79 (d, 2H), 4.45 ( s, 2H), 3.46-3.85 (m, 4H), 3.09 (t, 2H), 2.91 (s, 6H), 2.22-2.54 (m, 8H), 1.73-2.06 (m, 2H).

ステップ１：
４-(５-ブロモピリジン-２-イルメチル)ピペリジン-１-カルボン酸ｔｅｒｔ-ブチルエステル：

９-ＢＢＮの溶液(０.５Ｎ、ＴＨＦ中,１００ｍＬ)に、４-メチレンピペリジン-１-カルボン酸ｔｅｒｔ-ブチルエステル(１.２３ｇ、１.５ｍｍｏｌ)を加え、反応混合液を１時間還流して撹拌した。反応混合液を室温に冷却し、そしてシリンジを介してＤＭＦ(１００ｍｌ)及び水(９.９ｍｌ)及びＫ₂ＣＯ₃(８.２９ｇ)中に溶解された２,５-ジブロモピリジン(１１.３ｇ、４７.５ｍｍｏｌ)及びＰｄ(ｄｐｐｆ)Ｃｌ２ジクロロメタン(１.２３ｇ、１.５ｍｍｏｌ)の溶液に加えた。この混合物を６０℃で３時間加熱した。ＤＭＦそ吸引下で除いた。酢酸エチル／ヘプタンを加えて、幾つかの結晶を得た。その結果、粗製混合物を１回以上蒸発させて油にした。酢酸エチル／ヘプタン(９：１)を溶出液として用いたＣｏｍｂｉＦｌａｓｈ精製は、４-(５-ブロモピリジン-２-イルメチル)ピペリジン-１-カルボン酸ｔｅｒｔ-ブチルエステルを茶色の油として与えた。収率：８ｇ、(４５％)であった。
¹H NMR (400 MHz, CDCl₃) δ: 8.6(d, 1H), 7.7(d,d, 1H), 6.99(d, 1H), 4.1 (br. M, 2H), 2.6-2.7(m, 4H), 1.8-2.0(m, 2H), 1.5-1.6(m, 4H), 1.45(s, 9H). Example 27 (General production method B)
{4- [6- (1-Cyclobutylpiperidin-4-ylmethyl) pyridin-3-yl] phenyl}-(4-methylpiperazin-1-yl) -methanone, trihydrochloride:

Step 1 :
4- (5-Bromopyridin-2-ylmethyl) piperidine-1-carboxylic acid tert-butyl ester:

To a solution of 9-BBN (0.5N in THF, 100 mL) 4-methylenepiperidine-1-carboxylic acid tert-butyl ester (1.23 g, 1.5 mmol) was added and the reaction mixture was refluxed for 1 hour. And stirred. The reaction mixture was cooled to room temperature and 2,5-dibromopyridine (11.3 g) dissolved in DMF (100 ml) and water (9.9 ml) and K ₂ CO ₃ (8.29 g) via syringe. , 47.5 mmol) and Pd (dppf) Cl2 dichloromethane (1.23 g, 1.5 mmol). The mixture was heated at 60 ° C. for 3 hours. DMF was removed under suction. Ethyl acetate / heptane was added to give some crystals. As a result, the crude mixture was evaporated to an oil one or more times. CombiFlash purification using ethyl acetate / heptane (9: 1) as eluent gave 4- (5-bromopyridin-2-ylmethyl) piperidine-1-carboxylic acid tert-butyl ester as a brown oil. Yield: 8 g (45%).
^{1 H NMR (400 MHz, CDCl} 3) δ: 8.6 (d, 1H), 7.7 (d, d, 1H), 6.99 (d, 1H), 4.1 (. Br M, 2H), 2.6-2.7 (m, 4H), 1.8-2.0 (m, 2H), 1.5-1.6 (m, 4H), 1.45 (s, 9H).

４-(５-ブロモピリジン-２-イルメチル)ピペリジン-１-カルボン酸ｔｅｒｔ-ブチルエステル(８ｇ、２２.５ｍｍｏｌ)をＤＭＦ中に溶解し、ＴＦＡ(２５ｍｌ)を加えた。反応は発熱反応であり、そしていくらかのブタンが蒸発した。反応混合液を室温で１時間撹拌した。反応混合液を吸引下で蒸発させ、そしてアセトンで４回ストリップした。アミンを、茶色の油としてジトリフルオロ酢酸塩として単離した。収率：１０.９ｇ(１００％)。
ＬＣ-ＭＳ(エレクトロスプレー)：m/z: 255及び257(M+1)及び(M+2); Rt = 0.69分 Step 2 :
4- (5-Bromopyridin-2-ylmethyl) piperidine, ditrifluoroacetate:

4- (5-Bromopyridin-2-ylmethyl) piperidine-1-carboxylic acid tert-butyl ester (8 g, 22.5 mmol) was dissolved in DMF and TFA (25 ml) was added. The reaction was exothermic and some butane evaporated. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under suction and stripped 4 times with acetone. The amine was isolated as a ditrifluoroacetate salt as a brown oil. Yield: 10.9 g (100%).
LC-MS (electrospray): m / z: 255 and 257 (M + 1) and (M + 2); Rt = 0.69 min

４-(５-ブロモピリジン-２-イルメチル)ピペリジン,ジトリフルオロ酢酸(１０.９ｇ、２２.５ｍｍｏｌ)及びシクロブタノン(２.４ｇ,３４ｍｍｏｌ)を酢酸(４.２ｇ、６８mmol)及びＭｅＯＨ(１００ｍｌ)中に溶解した。水(２０ｍｌ)に溶解したＮａＣＮＢＨ₃(２.１ｇ、３４ｍｍｏｌ)を反応混合液に加えた。反応混合液を室温で一晩撹拌した。多くのシクロブタノン(１ｍｌ)とＮａＣＮＢＨ₃(８３０ｍｇ)が存在し、そして反応混合液を４０℃で４時間加熱した。反応混合液を吸引下で粘度の高い油へと蒸発させた。ＤＣＭ(１０ＯｍＬ)及び１Ｎ・ＮａＯＨ(１０ＯｍＬ)を加えた。有機相を、水(５０ｍｌ)と塩類溶液(５０ｍｌ)で洗浄した。Ｎａ₂ＳＯ₄で乾燥し、ろ過し、そして吸引下蒸発させて油にする。油をＣｏｍｂｉＦｌａｓｈ上で酢酸エチル、そして最終的に最大２０％のＭｅＯＨを伴う勾配で精製した。５-ブロモ-２-(１-シクロブチル-ピペリン-４-イルメチル)ピリジンを白色結晶として単離した(３７％)。
LC-MS (エレクトロスプレー): m/z: 309 (M+1); Rt = 0.88 分
¹H NMR (400 MHz, MeOH-D4) δ: 8.6(d, 1H), 7.7(d,d, 1H), 7.25(s, 1H), 7.0(d, 1H), 2.75(d, 2H), 2.65(m, 3H), 1.6-2.1 (m, 10H), 1.2-1.4(m, 3H). Step 3
5-Bromo-2- (1-cyclobutylpiperin-4-ylmethyl) pyridine:

4- (5-Bromopyridin-2-ylmethyl) piperidine, ditrifluoroacetic acid (10.9 g, 22.5 mmol) and cyclobutanone (2.4 g, 34 mmol) in acetic acid (4.2 g, 68 mmol) and MeOH (100 ml). Dissolved in. NaCNBH ₃ (2.1 g, 34 mmol) dissolved in water (20 ml) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. There was a lot of cyclobutanone (1 ml) and NaCNBH ₃ (830 mg) and the reaction mixture was heated at 40 ° C. for 4 hours. The reaction mixture was evaporated to a thick oil under suction. DCM (10OmL) and 1N NaOH (10OmL) were added. The organic phase was washed with water (50 ml) and brine (50 ml). Dry over Na ₂ SO ₄ , filter and evaporate under suction to an oil. The oil was purified on a CombiFlash with a gradient with ethyl acetate and finally up to 20% MeOH. 5-Bromo-2- (1-cyclobutyl-piperin-4-ylmethyl) pyridine was isolated as white crystals (37%).
LC-MS (electrospray): m / z: 309 (M + 1); Rt = 0.88 min
¹ H NMR (400 MHz, MeOH-D4) δ: 8.6 (d, 1H), 7.7 (d, d, 1H), 7.25 (s, 1H), 7.0 (d, 1H), 2.75 (d, 2H), 2.65 (m, 3H), 1.6-2.1 (m, 10H), 1.2-1.4 (m, 3H).

Step 4 :
5-Bromo-2- (1-cyclobutylpiperin-4-ylmethyl) pyridine (0.277 g, 0.89 mmol) and 4-((4-methyl-piperazin-1-yl) -4- (4,4, 5,5-Tetramethyl- [1,3,2] dioxoborolan-2-yl) phenyl) methanone (0.354 g, 1.075 mmol) was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of trihydrochloride. Yield 230 mg (47%).
LC-MS (electrospray): m / z: 433 (M + 1); Rt = 0.58 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.75 (d, d, 1H), 7.78 (d, d, 1H), 7.6 (d, 2H), 7.5 (d, 2H), 7.2 (d, 1H) , 3.8 (br. S, 2H), 3.5 (br. S, 2H), 2.85 (d, 2H), 2.75 (d, 2H), 2.65 (m, 1H), 2.3-2.6 (m, 2H), 2.3 (s, 3H), 2.0 (m, 2H), 1.8 (m, 4H), 1.65 (m, 4H), 1.45 (m, 2H).

５-ブロモ-２-(１-シクロブチルピペリン-４-イルメチル)ピリジン(０.２７７,０.８９ｍｍｏｌ)及びＮ,Ｎ-ジメチル-４-ボロノベンゼンスルホンアミド(０.２４６ｇ；１.０７５ｍｍｏｌ)を、触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：１９０ｍｇ(４４％)
LC-MS (エレクトロスプレー): m/z: 414 (M+1); Rt = 0.95 分
¹H NMR (400 MHz, CDCl₃) δ: 8.78(d, 1H), 7.88(d, 2H), 7.8(d,d, 1H), 7.74(d, 2H), 7.2(d, 1H), 2.85(br. d, 2H), 2.78(d, 2H), 2.7(s, 6H), 2.65(m, 1H), 2.0(m, 2H), 1.7-1.9(m, 4H), 1.6-1.7(m, 5H), 1.3-1.47(m, 2H). Example 28 (General production method B)
4- [6- (1-Cyclobutylpiperidin-4-ylmethyl) pyridin-3-yl] -N, N-dimethylbenzenesulfonamide, dihydrochloride:

5-Bromo-2- (1-cyclobutylpiperin-4-ylmethyl) pyridine (0.277, 0.89 mmol) and N, N-dimethyl-4-boronobenzenesulfonamide (0.246 g; 1.075 mmol) Was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 190 mg (44%)
LC-MS (electrospray): m / z: 414 (M + 1); Rt = 0.95 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.78 (d, 1H), 7.88 (d, 2H), 7.8 (d, d, 1H), 7.74 (d, 2H), 7.2 (d, 1H), 2.85 (br.d, 2H), 2.78 (d, 2H), 2.7 (s, 6H), 2.65 (m, 1H), 2.0 (m, 2H), 1.7-1.9 (m, 4H), 1.6-1.7 (m , 5H), 1.3-1.47 (m, 2H).

５-ブロモ-２-(１-シクロブチルピペリン-４-イルメチル)ピリジン(０.２７７,０.８９ｍｍｏｌ)及び２-メチル-４-ピリジンボロン酸(０.１４７ｇ；１.０７５ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：１９０ｍｇ(４４％)
LC-MS(エレクトロスプレー): m/z: 322 (M+1); Rt = 0.68 分
¹H NMR (400 MHz, CDCl₃) δ: 8.78(d,d, 1H), 8.55(d, 1H), 7.8(d,d, 1H), 7.45(s, 1H), 7.25(d, 1H), 7.22(d,d, 1H), 2.85(m, 2H), 2.75(d, 2H), 2.65(m, 1H), 2.62(s, 3H), 1.75-2.1 (m, 6H), 1.6- 1.75(m, 5H), 1.45(m, 2H). Example 29 (General production method B)
6- (1-Cyclobutylpiperidin-4-ylmethyl) -2'-methyl- [3,4 '] bipyridinyl, dihydrochloride:

5-Bromo-2- (1-cyclobutylpiperin-4-ylmethyl) pyridine (0.277, 0.89 mmol) and 2-methyl-4-pyridineboronic acid (0.147 g; 1.075 mmol) mixed with the catalyst And reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 190 mg (44%)
LC-MS (electrospray): m / z: 322 (M + 1); Rt = 0.68 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.78 (d, d, 1H), 8.55 (d, 1H), 7.8 (d, d, 1H), 7.45 (s, 1H), 7.25 (d, 1H) , 7.22 (d, d, 1H), 2.85 (m, 2H), 2.75 (d, 2H), 2.65 (m, 1H), 2.62 (s, 3H), 1.75-2.1 (m, 6H), 1.6- 1.75 (m, 5H), 1.45 (m, 2H).

５-ブロモ-２-(１-シクロブチルピペリン-４-イルメチル)ピリジン(０.５００,１.６１７ｍｍｏｌ)及びＮ,Ｎ-ジメチル-ベンズアミド-４-ボロン酸(０.３４７ｇ；１.９４ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：１６０ｍｇ(２６％)
LC-MS (エレクトロスプレー): m/z: 322 (M+1); Rt = 0.68 分
¹H NMR (400 MHz, CDCl₃) δ: 8.77(d, 1H), 7.78(d,d, 1H), 7.60(d, 2H), 7.35(d, 2H), 7.20(d, 1H), 3.14(s, 3H), 3.04(s, 3H), 2.86(d, 2H), 2.76(d, 2H), 2.60-2.69(m, 1H), 1.96-2.07(m, 1H), 1.79-1.93(m, 3H), 1.62-1.71 (m, 6H), 1.31-1.43(m, 2H). Example 30 (General production method B)
4- [6- (1-Cyclobutylpiperidin-4-ylmethyl) pyridin-3-yl] -N, N-dimethylbenzamide, dihydrochloride:

5-Bromo-2- (1-cyclobutylpiperin-4-ylmethyl) pyridine (0.500, 1.617 mmol) and N, N-dimethyl-benzamido-4-boronic acid (0.347 g; 1.94 mmol) were added. Mixed with catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 160 mg (26%)
LC-MS (electrospray): m / z: 322 (M + 1); Rt = 0.68 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.77 (d, 1H), 7.78 (d, d, 1H), 7.60 (d, 2H), 7.35 (d, 2H), 7.20 (d, 1H), 3.14 (s, 3H), 3.04 (s, 3H), 2.86 (d, 2H), 2.76 (d, 2H), 2.60-2.69 (m, 1H), 1.96-2.07 (m, 1H), 1.79-1.93 (m , 3H), 1.62-1.71 (m, 6H), 1.31-1.43 (m, 2H).

５-ブロモ-２-(１-シクロブチルピペリン-４-イルメチル)ピリジン(０.３２０,１.０３５ｍｍｏｌ)及びＮ-モルホリニル-１-カルボニルフェニル-４-ボロン酸(０.２９２ｇ；１.２４ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：２００ｍｇ(４６％)
LC-MS (エレクトロスプレー): m/z: 420 (M+1); Rt = 0.68 分
¹H NMR (400 MHz, CDCl₃) δ: 8.76(d, 1H), 8.08(d,d, 1H), 7.62(d, 2H), 7.52(d, 2H), 7.2(d, 1H), 3.44-3.83(m, 8H), 2.86(d, 2H), 2.77(d, 2H), 2.58-2.71 (m, 1H), 1.94-2.1 (m, 2H), 1.8- 1.92(m, 3H), 1.63-1.75(m, 6H), 130-1.48(m, 2H). Example 31 (General production method B)
{4- [6- (1-Cyclobutylpiperidin-4-ylmethyl) pyridin-3-yl] phenyl} morpholin-4-ylmethanone, dihydrochloride:

5-Bromo-2- (1-cyclobutylpiperin-4-ylmethyl) pyridine (0.320, 1.035 mmol) and N-morpholinyl-1-carbonylphenyl-4-boronic acid (0.292 g; 1.24 mmol) Was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 200 mg (46%)
LC-MS (electrospray): m / z: 420 (M + 1); Rt = 0.68 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.76 (d, 1H), 8.08 (d, d, 1H), 7.62 (d, 2H), 7.52 (d, 2H), 7.2 (d, 1H), 3.44 -3.83 (m, 8H), 2.86 (d, 2H), 2.77 (d, 2H), 2.58-2.71 (m, 1H), 1.94-2.1 (m, 2H), 1.8- 1.92 (m, 3H), 1.63 -1.75 (m, 6H), 130-1.48 (m, 2H).

４-［６-(１-シクロブチルピペリジン-４-イルメチル)ピリジン-３-イル］-Ｎ,Ｎ-ジメチルベンズアミド(０.１６０ｇ、０.４２４ｍｍｏｌ)を、乾燥ＴＨＦ(１０ｍｌ)中に溶解し、実施例２４と同じ様式で反応させ、そして精製した。
収率：２５ｍｇ(１６％)トリヒドロクロリドの白色結晶
LC-MS (エレクトロスプレー): m/z: 374 (M+1); Rt = 0.99 分
¹H NMR (400 MHz, MeOH-D4) δ: 9.15(d, 1H), 8.9(d, 1H), 8.15(s, 1H), 7.95(d, 2H), 7.75(d, 2H), 4.45(m, 2H), 3.65(m, 1H), 3.45(m, 2H), 3.15(m, 2H), 2.9(s, 6H), 2.75-2.9(m, 2H), 2.2-2.45(m, 6H), 1.7-2.1 (m, 4H). Example 32 (General production method B)
{4- [6- (1-Cyclobutylpiperidin-4-ylmethyl) pyridin-3-yl] benzyl} dimethylamine, trihydrochloride:

4- [6- (1-Cyclobutylpiperidin-4-ylmethyl) pyridin-3-yl] -N, N-dimethylbenzamide (0.160 g, 0.424 mmol) was dissolved in dry THF (10 ml), Reacted and purified in the same manner as Example 24.
Yield: 25 mg (16%) white crystals of trihydrochloride
LC-MS (electrospray): m / z: 374 (M + 1); Rt = 0.99 min
¹ H NMR (400 MHz, MeOH-D4) δ: 9.15 (d, 1H), 8.9 (d, 1H), 8.15 (s, 1H), 7.95 (d, 2H), 7.75 (d, 2H), 4.45 ( m, 2H), 3.65 (m, 1H), 3.45 (m, 2H), 3.15 (m, 2H), 2.9 (s, 6H), 2.75-2.9 (m, 2H), 2.2-2.45 (m, 6H) , 1.7-2.1 (m, 4H).

５-ブロモ-２-(１-シクロブチルピペリン-４-イルメチル)ピリジン(０.３６０,０.８４１５ｍｍｏｌ)及び４-エタン-スルホニルフェニルボロン酸(０.１９７ｇ；０.９２５ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：６２ｍｇ(１６％)
LC-MS (エレクトロスプレー): m/z: 399 (M+1); Rt = 0.84 分
¹H NMR (400 MHz, CDCl₃) δ: 8.8(d, 1H), 8.0(d,d, 2H), 7.8(d,d, 1H), 7.75(d, 2H), 7.25(d, 1H), 3.15(q, 2H), 2.85(br.d, 2H), 2.78(d, 2H), 2.65(m, 1H), 2.05(m, 2H), 1.75-1.95(m, 2H), 1.55- 1.75(7H), 1.35-1.45(m, 2H), 1.3(t, 3H). Example 33 (General production method B)
2- (1-Cyclobutylpiperidin-4-ylmethyl) -5- (4-ethanesulfonylphenyl) pyridine, dihydrochloride:

5-Bromo-2- (1-cyclobutylpiperin-4-ylmethyl) pyridine (0.360, 0.8415 mmol) and 4-ethane-sulfonylphenylboronic acid (0.197 g; 0.925 mmol) were mixed with the catalyst. And reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 62 mg (16%)
LC-MS (electrospray): m / z: 399 (M + 1); Rt = 0.84 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.8 (d, 1H), 8.0 (d, d, 2H), 7.8 (d, d, 1H), 7.75 (d, 2H), 7.25 (d, 1H) , 3.15 (q, 2H), 2.85 (br.d, 2H), 2.78 (d, 2H), 2.65 (m, 1H), 2.05 (m, 2H), 1.75-1.95 (m, 2H), 1.55- 1.75 (7H), 1.35-1.45 (m, 2H), 1.3 (t, 3H).

訂正：この式において、水素原子は、アセトアミド基の窒素原子に付加されるべきである。
ステップ１：
１-(６-クロロピリジン-３-イルメチル)-４-イソプロピルピペラジン：

イソプロピルピペラジン(２.３ｇ、１７.９４ｍｍｏｌ)、２-クロロ-５-クロロメチルピリジン(３.２ｇ、１９.７３ｍｍｏｌ)及びＫ₂ＣＯ₃(２６.９１ｇ、３.７１３ｍｍｏｌ)を、ＥｔＯＨ(５０ｍｌ)中に混合した。強い発熱反応であった。当該反応液をさらに６５℃で12時間加熱した。反応混合液をろ過し、そして蒸発させた。粗製生成物を、さらに精製することなく用いた。
HPLC (方法C) Rt= 0.49 min, 純度＞９２％. Example 34 (General manufacturing method F)
N- {4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] phenyl} acetamide, trihydrochloride:

Correction: In this formula, a hydrogen atom should be added to the nitrogen atom of the acetamide group.
Step 1 :
1- (6-Chloropyridin-3-ylmethyl) -4-isopropylpiperazine:

Isopropylpiperazine (2.3 g, 17.94 mmol), 2-chloro-5-chloromethylpyridine (3.2 g, 19.73 mmol) and K ₂ CO ₃ (26.91 g, 3.713 mmol) were added to EtOH (50 ml). Mixed in. It was a strong exothermic reaction. The reaction was further heated at 65 ° C. for 12 hours. The reaction mixture was filtered and evaporated. The crude product was used without further purification.
HPLC (Method C) Rt = 0.49 min, purity> 92%.

Step 2 :
1- (6-chloropyridin-3-ylmethyl) -4-isopropylpiperazine (0.2 g, 0.788 mmol) and 4-acetamido-phenylboronic acid (0.155 g, 0.867 mmol) are mixed with the catalyst, and The reaction was carried out in the same manner as in Example 18. The title compound was isolated as yellow crystals of the trihydrochloride salt. Yield: 231 mg (64%).

LC-MS (electrospray): m / z: 353 (M + 1); Rt = 0.667 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.7 (s, 1H), 8.5 (d, d, 1H), 8.2 (d, 1H), 7.77 (d, 2H), 7.6 (d, 2H), 4.2 (s, 2H), 2.9-3.6 (m, 9H), 2.1 (s, 3H), 1.2 (d, 6H).

訂正：この式において、２つの水素原子が、ベンゼン環に結合した窒素に結合されているべきである。
Ｎ-｛４-［５-(４-イソプロピルピペラジン-１-イルメチル)ピリジン-２-イル］フェニル｝アセトアミド,トリフルオロ酢酸((０.４２７ｇ、０.９２ｍｍｏｌ)を電磁波バイアル(５ｍｌ)中に入れた１Ｎ・ＨＣｌ(５ｍｌ)に溶解した。反応混合液を１３０℃で９００秒加熱した。反応混合液を吸引下で蒸発させて、標題の化合物を三塩酸塩黄色結晶３９７ｍｇ(９５％)として与えた。
LC-MS (エレクトロスプレー): m/z: 311 (M+1); Rt = 0.532 分 HPLC (方法C) Rt = 0.48分, 純度 = 100%. Example 35 (General production method F)
4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] phenylamine, trihydrochloride:

Correction: In this formula, two hydrogen atoms should be bound to the nitrogen bound to the benzene ring.
N- {4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] phenyl} acetamide, trifluoroacetic acid ((0.427 g, 0.92 mmol) was placed in an electromagnetic wave vial (5 ml). The reaction mixture was heated for 900 seconds at 130 ° C. The reaction mixture was evaporated under suction to give the title compound as the trihydrochloride yellow crystals 397 mg (95%). It was.
LC-MS (electrospray): m / z: 311 (M + 1); Rt = 0.532 min HPLC (Method C) Rt = 0.48 min, purity = 100%.

１-(６-クロロピリジン-３-イルメチル)-４-イソプロピルピペラジン(０.２ｇ,０.７８８ｍｍｏｌ)及び４-エチルスルホニル-フェニルボロン酸(０.１８６ｇ,０.８６７ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：２６０ｍｇ(７２％)
LC-MS (エレクトロスプレー): m/z: 388 (M+1); Rt = 0.867 分
¹H NMR (400 MHz, DMSO-D6) δ: 8.83(s, 1H), 8.28(d, 2H), 8.2(m, 2H), 8.0(d, 2H), 4.5(s, 2H), 3.4-3.65(m, 8H), 3.3(q, 2H), 1.25(d, 6H), 1.1 (t, 3H). Example 36 (General production method F)
1- [6- (4-ethanesulfonylphenyl) pyridin-3-ylmethyl] -4-isopropylpiperazine, dihydrochloride:

1- (6-chloropyridin-3-ylmethyl) -4-isopropylpiperazine (0.2 g, 0.788 mmol) and 4-ethylsulfonyl-phenylboronic acid (0.186 g, 0.867 mmol) were mixed with the catalyst, The reaction was then carried out in the same manner as in Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 260 mg (72%)
LC-MS (electrospray): m / z: 388 (M + 1); Rt = 0.867 min
¹ H NMR (400 MHz, DMSO-D6) δ: 8.83 (s, 1H), 8.28 (d, 2H), 8.2 (m, 2H), 8.0 (d, 2H), 4.5 (s, 2H), 3.4- 3.65 (m, 8H), 3.3 (q, 2H), 1.25 (d, 6H), 1.1 (t, 3H).

１-(６-クロロピリジン-３-イルメチル)-４-イソプロピルピペラジン(０.２ｇ,０.７８８ｍｍｏｌ)及び４-(１-ピペリジニル-スルホニル)フェニルボロン酸(０.２３３ｇ,０.８６７ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：２９５ｍｇ(７３％)
LC-MS (エレクトロスプレー): m/z: 443 (M+1); Rt = 1.134 分
¹H NMR (400 MHz, DMSO-D6) δ: 8.82(d, 1H), 8.32(d,d, 1H), 8.2-8.25(m, 3H), 7.96(d, 2H), 4.15(s, 2H), 3.3-3.7(m, 7H), 3.05-3.25(m, 2H), 3.05(m, 4H), 1.65(m, 4H), 1.45(m, 2h9, 1.4(d,6H). Example 37 (General manufacturing method F)
1-isopropyl-4- {6- [4- (piperidin-1-sulfonyl) phenyl] pyridin-3-ylmethyl} piperazine, dihydrochloride:

Catalyzed 1- (6-chloropyridin-3-ylmethyl) -4-isopropylpiperazine (0.2 g, 0.788 mmol) and 4- (1-piperidinyl-sulfonyl) phenylboronic acid (0.233 g, 0.867 mmol) And reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 295 mg (73%)
LC-MS (electrospray): m / z: 443 (M + 1); Rt = 1.134 min
¹ H NMR (400 MHz, DMSO-D6) δ: 8.82 (d, 1H), 8.32 (d, d, 1H), 8.2-8.25 (m, 3H), 7.96 (d, 2H), 4.15 (s, 2H ), 3.3-3.7 (m, 7H), 3.05-3.25 (m, 2H), 3.05 (m, 4H), 1.65 (m, 4H), 1.45 (m, 2h9, 1.4 (d, 6H).

１-(６-クロロピリジン-３-イルメチル)-４-イソプロピルピペラジン(０.２ｇ,０.７８８ｍｍｏｌ)及び２-メチルピリジン-４-ボロン酸(０.１１９ｇ,０.８６７ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を三塩酸塩の白色結晶として単離した。収率：２９５ｍｇ(７３％)
LC-MS (エレクトロスプレー): m/z: 311 (M+1); Rt = 0.337 分
¹H NMR (400 MHz, MeOH-D4) δ: 9.15(s, 1H), 8.8(d, 1H), 8.7(s, 1H), 8.65(d, 1H), 8.45(br.s, 2H), 4.75(s, 2H), 3.6-3.9(m, 9H), 2.9(s, 3H), 1.45(d, 6H). Example 38 (General production method F)
5- (4-Isopropylpiperazin-1-ylmethyl) -2'-methyl- [2,4 '] bipyridinyl, trihydrochloride:

1- (6-Chloropyridin-3-ylmethyl) -4-isopropylpiperazine (0.2 g, 0.788 mmol) and 2-methylpyridine-4-boronic acid (0.119 g, 0.867 mmol) were mixed with the catalyst. And reacted in the same manner as Example 18. The title compound was isolated as white crystals of the trihydrochloride salt. Yield: 295 mg (73%)
LC-MS (electrospray): m / z: 311 (M + 1); Rt = 0.337 min
¹ H NMR (400 MHz, MeOH-D4) δ: 9.15 (s, 1H), 8.8 (d, 1H), 8.7 (s, 1H), 8.65 (d, 1H), 8.45 (br.s, 2H), 4.75 (s, 2H), 3.6-3.9 (m, 9H), 2.9 (s, 3H), 1.45 (d, 6H).

１-(６-クロロピリジン-３-イルメチル)-４-イソプロピルピペラジン(０.２ｇ,０.７８８ｍｍｏｌ)及び３,４-メチレンジオキシフェニルボロン酸(０.１４４ｇ,０.８６７ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の黄色結晶として単離した。収率：２２５ｍｇ(６９％)
LC-MS (エレクトロスプレー): m/z: 340 (M+1); Rt = 0.788 分
¹H NMR (400 MHz, MeOH-D4) δ: 9.15(s, 1H), 8.85(d, 1H), 8.4(d, 1H), 7.6(d, 1H), 7.55(s, 1H), 7.15(d, 1H), 6.15(s, 2H), 4.2(s, 2H), 3.6-3.8(m, 9H), 1.45(d, 6H) Example 39 (General production method F)
1- (6-1,3-Benzodioxol-5-ylpyridin-3-ylmethyl) -4-isopropylpiperazine, dihydrochloride:

1- (6-Chloropyridin-3-ylmethyl) -4-isopropylpiperazine (0.2 g, 0.788 mmol) and 3,4-methylenedioxyphenylboronic acid (0.144 g, 0.867 mmol) mixed with catalyst And reacted in the same manner as Example 18. The title compound was isolated as yellow crystals of dihydrochloride. Yield: 225 mg (69%)
LC-MS (electrospray): m / z: 340 (M + 1); Rt = 0.788 min
¹ H NMR (400 MHz, MeOH-D4) δ: 9.15 (s, 1H), 8.85 (d, 1H), 8.4 (d, 1H), 7.6 (d, 1H), 7.55 (s, 1H), 7.15 ( d, 1H), 6.15 (s, 2H), 4.2 (s, 2H), 3.6-3.8 (m, 9H), 1.45 (d, 6H)

１-(６-クロロピリジン-３-イルメチル)-４-イソプロピルピペラジン(０.２ｇ、０.７８８ｍｍｏｌ)及び４-モルホリノ-フェニルボロン酸(０.１７９ｇ、０.８６７ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の黄色結晶として単離した。収率：２１６ｍｇ(５２％)
LC-MS (エレクトロスプレー): m/z: 381 (M+1); Rt = 0.79 分
¹H NMR (400 MHz, MeOH-D4) δ: 8.48(s, 1H), 7.75-7.85(m, 4H), 7.05(d, 2H), 3.83(m, 4H), 3.68(s, 2H), 3.22(, 4H), 2.4-2.7(m, 9H), 1.05(d, 6H). Example 40 (General manufacturing method F)
4- {4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] phenyl} morpholine, dihydrochloride:

1- (6-chloropyridin-3-ylmethyl) -4-isopropylpiperazine (0.2 g, 0.788 mmol) and 4-morpholino-phenylboronic acid (0.179 g, 0.867 mmol) are mixed with the catalyst, and The reaction was carried out in the same manner as in Example 18. The title compound was isolated as yellow crystals of dihydrochloride. Yield: 216 mg (52%)
LC-MS (electrospray): m / z: 381 (M + 1); Rt = 0.79 min
¹ H NMR (400 MHz, MeOH-D4) δ: 8.48 (s, 1H), 7.75-7.85 (m, 4H), 7.05 (d, 2H), 3.83 (m, 4H), 3.68 (s, 2H), 3.22 (, 4H), 2.4-2.7 (m, 9H), 1.05 (d, 6H).

ステップ１：
１-(５-ブロモピリジン-２-イルメチル)-４-シクロブチルピペラジン：

１-(５-ブロモピリジン-２-イルメチル)ピペラジン(１０ｇ、３９.０４ｍｍｏｌ)をＴＨＦ(６５ｍｌ)、水(０.６ｍＬ)、シクロブタノン(４.１ｇ、５８.６ｍｍｏｌ)及び酢酸(７.５ｇ、１２５ｍｍｏｌ)中に混合した。次に、１Ｍ ＮａＣＮＢＨ₃を含むＴＨＦ(３.６８ｇ、５８ｍｍｏｌ)(５８ｍＬ)を加えた。次に反応混合液を加熱し、そして混合物中の残りの物質を溶解するために２１等量の水を加えた。反応混合液を６２℃で１.５時間加熱した(ＬＣ-ＭＳは、完全な変換を示した)。反応混合液を６２℃で一晩静置した。反応混合液にＤＣＭ(１５０ｍｌ)と水(１００ｍｌ)を加えた。４ＮのＮａＯＨでｐＨを１０に調整した。ＤＣＭを用いて水相を抽出した(２×２５ｍｌ)。組み合わせたＤＣＭ相を水(２×２５ｍｌ)、塩類溶液(２×２５ｍｌ)で洗浄し、最終的にＭｇＳＯ₄を用いて乾燥させ、ろ過し、そして吸引下で蒸発させて、７.６５ｇ(６３％)の粘度の高い油を与えた。
LC-MS (エレクトロスプレー): m/z: 312 (M+2); Rt = 0.74 分
¹H NMR (400 MHz, CDCl₃) δ: 8.6(d, 1H), 7.78(d,d, 1H), 7.3(d, 1H), 3.6(s, 2H), 2.85-2.95(m, 1H), 2.75(m, 1H), 2.3-2.65(m, 7H), 2.05(m, 2H), 1.9(m, 2H), 1.7(m, 2H). Example 41 (General manufacturing method F)
4- [6- (4-Cyclobutylpiperazin-1-ylmethyl) pyridin-3-yl] -N, N-dimethylbenzamide, dihydrochloride:

Step 1 :
1- (5-Bromopyridin-2-ylmethyl) -4-cyclobutylpiperazine:

1- (5-Bromopyridin-2-ylmethyl) piperazine (10 g, 39.04 mmol) in THF (65 ml), water (0.6 mL), cyclobutanone (4.1 g, 58.6 mmol) and acetic acid (7.5 g, 125 mmol). Next, THF (3.68 g, 58 mmol) (58 mL) containing 1 M NaCNBH ₃ was added. The reaction mixture was then heated and 21 equivalents of water was added to dissolve the remaining material in the mixture. The reaction mixture was heated at 62 ° C. for 1.5 hours (LC-MS showed complete conversion). The reaction mixture was left at 62 ° C. overnight. DCM (150 ml) and water (100 ml) were added to the reaction mixture. The pH was adjusted to 10 with 4N NaOH. The aqueous phase was extracted with DCM (2 × 25 ml). The combined DCM phases were washed with water (2 × 25 ml), brine (2 × 25 ml), finally dried with MgSO ₄ , filtered and evaporated under suction to give 7.65 g (63 %) High viscosity oil.
LC-MS (electrospray): m / z: 312 (M + 2); Rt = 0.74 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.6 (d, 1H), 7.78 (d, d, 1H), 7.3 (d, 1H), 3.6 (s, 2H), 2.85-2.95 (m, 1H) , 2.75 (m, 1H), 2.3-2.65 (m, 7H), 2.05 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).

Step 2 :
1- (5-Bromopyridin-2-ylmethyl) -4-cyclobutylpiperazine (0.596 g, 2 mmol) and N, N-dimethyl-benzamido-4-boronic acid (0.463 g; 2.4 mmol) as catalyst Mixed and reacted in the same manner as Example 18. The title compound was isolated as yellow crystals of dihydrochloride. Yield: 455 mg (50%)
LC-MS (electrospray): m / z: 379 (M + 1); Rt = 0.78 min
¹ H NMR (400 MHz, MeOH-D4) δ: DMSO; 9.05 (m, 1H), 8.37 (m, 1H), 7.87 (m, 3H), 7.57 (m, 2H), 4.60 (s, 2H), 3.78 (m, 1H), 3.68 (m, 2H), 3.55 (m, 4H), 3.33 (m, 2H), 3.01 (s, 3H), 2.95 (s, 3H), 2.39 (m, 2H), 2.16 (m, 2H), 1.73 (m, 2H).

ステップ１：
１-(５-ブロモピリジン-２-イルメチル)-４-イソプロピルピペラジン：

１-(５-ブロモピリジン-２-イルメチル)ピペラジン(１０ｇ、３９.０４ｍｍｏｌ)をＴＨＦ(６５ｍｌ)、水(０.６ｍＬ)、プロパノン(４.５ｇ、７８.０８ｍｍｏｌ)及び酢酸(７.５ｇ、１２５ｍｍｏｌ)中に溶解し、混合した。次に１Ｍ・ＮａＣＮＢＨ₃を含むＴＨＦ(３.６８ｇ、５８ｍｍｏｌ)(５８ｍＬ)を加えた。次に反応混合液を加熱し、そして混合液中の残りの物質を溶解するために２１等量の水を加えた。反応混合液を４５℃で一晩撹拌した。反応混合液にＤＣＭ(１５０ｍｌ)及び水(１００ｍｌ)を加えた。４Ｎ・ＮａＯＨを用いてｐＨを１-に調節した。水相をＤＣＭ(２×２５ｍｌ)で抽出した。併せたＤＣＭ相を水(２×２５ｍｌ)、塩類溶液(２×２５ｍｌ)で洗浄し、ＭｇＳＯ₄で乾燥させ、ろ過し、そして吸引下で蒸発させて、７.５６ｇ(６５％)の粘度の高い油を与えた。
LC-MS (エレクトロスプレー): m/z: 298 (M+1); Rt = 0.67 分
¹H NMR (400 MHz, ＣＤＣｌ₃) δ: 8.62(d, １Ｈ), 7.78(d,d, １Ｈ), 7.3(d, １Ｈ), 3.65(s, 2H), 2.75(m, １Ｈ), 2.55-2.7(m, 8H), 1.1 (d, 6H). Example 42 (General manufacturing method F)
4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridin-3-yl] -N, N-dimethylbenzamide, dihydrochloride:

Step 1 :
1- (5-Bromopyridin-2-ylmethyl) -4-isopropylpiperazine:

1- (5-Bromopyridin-2-ylmethyl) piperazine (10 g, 39.04 mmol) in THF (65 ml), water (0.6 mL), propanone (4.5 g, 78.08 mmol) and acetic acid (7.5 g, 125 mmol) and mixed. Next, THF (3.68 g, 58 mmol) (58 mL) containing 1 M NaCNBH ₃ was added. The reaction mixture was then heated and 21 equivalents of water was added to dissolve the remaining material in the mixture. The reaction mixture was stirred at 45 ° C. overnight. To the reaction mixture was added DCM (150 ml) and water (100 ml). The pH was adjusted to 1- using 4N NaOH. The aqueous phase was extracted with DCM (2 × 25 ml). The combined DCM phases were washed with water (2 × 25 ml), brine (2 × 25 ml), dried over MgSO ₄ , filtered and evaporated under suction to a 7.56 g (65%) viscosity. Gave high oil.
LC-MS (electrospray): m / z: 298 (M + 1); Rt = 0.67 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.62 (d, 1H), 7.78 (d, d, 1H), 7.3 (d, 1H), 3.65 (s, 2H), 2.75 (m, 1H), 2.55 -2.7 (m, 8H), 1.1 (d, 6H).

Step 2 :
Catalyzed 1- (5-bromopyridin-2-ylmethyl) -4-isopropylpiperazine (0.596, 2.0 mmol) and N, N-dimethyl-benzamido-4-boronic acid (0.463 g; 2.4 mmol) And reacted in the same manner as Example 18. The title compound was isolated as yellow crystals of dihydrochloride. Yield: 136 mg (19%)
LC-MS (electrospray): m / z: 367 (M + 1); Rt = 0.74 min
¹ H NMR (400 MHz, D2O) δ: 8.96 (d, 1H), 8.67 (dd, 1H), 7.98 (d, 1H), 7.80 (d, 2H), 7.56 (d, 2H), 4.17 (s, 2H), 3.62 (m, 3H), 3.26 (m, Broad, 4H), 3.06 (s, 3H), 2.97 (s, 3H), 2.86 (m, Broad, 2H), 1.32 (m, 6H).

１-(５-ブロモピリジン-２-イルメチル)-４-シクロブチルピペラジン(０.６２、２.０ｍｍｏｌ)及び４-エチルスルホニル-フェニルボロン酸(０.５１４ｇ、２.４ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：２６０ｍｇ(２８％)
LC-MS (エレクトロスプレー): m/z: 400 (M+1); Rt = 0.86 分
¹H NMR (400 MHz, D2O) δ: 9.13 (d, １Ｈ), 8.79 (dd, １Ｈ), 8.15 (m, 3H), 8.08 (d, 2H), 4.41 (s, 2H), 3.87 (m, １Ｈ), 3.68 (m, ブロード, 2H), 3.48 (m, 2H), 3.42 (m, ブロード, 2H), 3.25 (m, ブロード, 2H), 3.06 (m, ブロード, 2H), 2.45 (m, 2H), 2.30 (m, 2H), 1.95 (m, 2H), 1.33 (t, 3H). Example 43 (General manufacturing method F)
1-cyclobutyl-4- [5- (4-ethanesulfonylphenyl) pyridin-2-ylmethyl] piperazine, dihydrochloride:

1- (5-Bromopyridin-2-ylmethyl) -4-cyclobutylpiperazine (0.62, 2.0 mmol) and 4-ethylsulfonyl-phenylboronic acid (0.514 g, 2.4 mmol) were mixed with the catalyst. And reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 260 mg (28%)
LC-MS (electrospray): m / z: 400 (M + 1); Rt = 0.86 min
¹ H NMR (400 MHz, D2O) δ: 9.13 (d, 1H), 8.79 (dd, 1H), 8.15 (m, 3H), 8.08 (d, 2H), 4.41 (s, 2H), 3.87 (m, 1H), 3.68 (m, Broad, 2H), 3.48 (m, 2H), 3.42 (m, Broad, 2H), 3.25 (m, Broad, 2H), 3.06 (m, Broad, 2H), 2.45 (m, 2H), 2.30 (m, 2H), 1.95 (m, 2H), 1.33 (t, 3H).

１-(５-ブロモピリジン-２-イルメチル)-４-イソプロピルピペラジン(０.５９６、２.０ｍｍｏｌ)及び４-エチルスルホニル-フェニルボロン酸(０.５１４ｇ、２.４ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：１４０ｍｇ(２８％)
LC-MS (エレクトロスプレー): m/z: 388 (M+1); Rt = 0.83 分
¹H NMR (400 MHz, D2O) δ: 8.92 (d, １Ｈ), 8.56 (dd, １Ｈ), 7.93 (m, 3H), 7.87 (m, 2H), 4.21 (s, 2H), 3.49 (q, 3H), 3.29 (Q, 6H), 2.91 (m, ブロード, 2H), 1.26 (d, 6H), 1.11 (t, 3H). Example 44 (General manufacturing method F)
1- [5- (4-Ethansulfonylphenyl) pyridin-2-ylmethyl] -4-isopropylpiperazine, dihydrochloride:

1- (5-Bromopyridin-2-ylmethyl) -4-isopropylpiperazine (0.596, 2.0 mmol) and 4-ethylsulfonyl-phenylboronic acid (0.514 g, 2.4 mmol) were mixed with the catalyst, The reaction was then carried out in the same manner as in Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 140 mg (28%)
LC-MS (electrospray): m / z: 388 (M + 1); Rt = 0.83 min
¹ H NMR (400 MHz, D2O) δ: 8.92 (d, 1H), 8.56 (dd, 1H), 7.93 (m, 3H), 7.87 (m, 2H), 4.21 (s, 2H), 3.49 (q, 3H), 3.29 (Q, 6H), 2.91 (m, Broad, 2H), 1.26 (d, 6H), 1.11 (t, 3H).

１-(５-ブロモピリジン-２-イルメチル)-４-シクロブチルピペラジン(０.６２、２.０ｍｍｏｌ)及び４-((４-メチル-ピペラジン-１-イル)-４-(４,４,５,５-テトラメチル-［１,３,２］ジオキソボロラン-２-イル)フェニル)メタノン(０.７３ｇ、２.４ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を三塩酸塩の白色結晶として単離した。収率：２６０ｍｇ(２８％)
LC-MS (エレクトロスプレー): m/z: 434 (M+1); Rt = 0.57 分
¹H NMR (400 MHz, D2O) δ: 9.05 (d, １Ｈ), 8.63 (d,d, １Ｈ), 7.98 (d, １Ｈ), 7.92 (d, 2H), 7.70 (d, 2H), 4.19 (s, 2H), 3.78 (m, １Ｈ), 3.54 (m, ブロード, 8H), 3.24 (m, ブロード, 6H), 2.96 (s, 3H), 2.92 (m, ブロード, 2H), 2.35 (m, 4H), 1.91 (m, 2H). Example 45 (General production method F)
{4- [6- (4-Cyclobutylpiperazin-1-ylmethyl) pyridin-3-yl] phenyl}-(4-methylpiperazin-1-yl) -methanone, trihydrochloride:

1- (5-Bromopyridin-2-ylmethyl) -4-cyclobutylpiperazine (0.62, 2.0 mmol) and 4-((4-methyl-piperazin-1-yl) -4- (4,4, 5,5-Tetramethyl- [1,3,2] dioxoborolan-2-yl) phenyl) methanone (0.73 g, 2.4 mmol) was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the trihydrochloride salt. Yield: 260 mg (28%)
LC-MS (electrospray): m / z: 434 (M + 1); Rt = 0.57 min
¹ H NMR (400 MHz, D2O) δ: 9.05 (d, 1H), 8.63 (d, d, 1H), 7.98 (d, 1H), 7.92 (d, 2H), 7.70 (d, 2H), 4.19 ( s, 2H), 3.78 (m, 1H), 3.54 (m, Broad, 8H), 3.24 (m, Broad, 6H), 2.96 (s, 3H), 2.92 (m, Broad, 2H), 2.35 (m, 4H), 1.91 (m, 2H).

１-(５-ブロモピリジン-２-イルメチル)-４-イソプロピルピペラジン(０.５９６、２.０ｍｍｏｌ)及び４-((４-メチル-ピペラジン-１-イル)-４-(４,４,５,５-テトラメチル-［１,３,２］ジオキソボロラン-２-イル)フェニル)メタノン(０.７３ｇ、２.４ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を三塩酸塩の白色結晶として単離した。収率：２２６ｍｇ(２３％)
LC-MS (エレクトロスプレー): m/z: 422 (M+1); Rt = 0.55 分
¹H NMR (400 MHz, CDCl₃) δ: 8.80 (d, 1H), 7.85 (dd, 1H), 7.61 (d. 2H), 7.50 (m, 3H), 3.83 (m,ブロード, 2H), 3.62 (s, 2H), 3.50 (m,ブロード, 2H), 2.69 (m, 1H), 2.62 (m,ブロード, 8H), 2.50 (m,ブロード, 2H), 2.38 (m,ブロード, 2H), 2.34 (s, 3H), 1.07 (d, 6H). Example 46 (General manufacturing method F)
{4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridin-3-yl] phenyl}-(4-methylpiperazin-1-yl) -methanone, trihydrochloride:

1- (5-Bromopyridin-2-ylmethyl) -4-isopropylpiperazine (0.596, 2.0 mmol) and 4-((4-methyl-piperazin-1-yl) -4- (4,4,5 , 5-Tetramethyl- [1,3,2] dioxoborolan-2-yl) phenyl) methanone (0.73 g, 2.4 mmol) was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the trihydrochloride salt. Yield: 226 mg (23%)
LC-MS (electrospray): m / z: 422 (M + 1); Rt = 0.55 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.80 (d, 1H), 7.85 (dd, 1H), 7.61 (d. 2H), 7.50 (m, 3H), 3.83 (m, broad, 2H), 3.62 (s, 2H), 3.50 (m, Broad, 2H), 2.69 (m, 1H), 2.62 (m, Broad, 8H), 2.50 (m, Broad, 2H), 2.38 (m, Broad, 2H), 2.34 (s, 3H), 1.07 (d, 6H).

１-(６-クロロピリジン-３-イルメチル)-４-イソプロピルピペラジン(０.５ｇ、１.９７ｍｍｏｌ)及び４-((４-メチル-ピペラジン-１-イル)-４-(４,４,５,５-テトラメチル-［１,３,２］ジオキソボロラン-２-イル)フェニル)メタノン(０.７１６ｇ、２.２ｍｍｏｌ))を、触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を三塩酸塩の白色結晶として単離した。収率：１.０ｇ(９６％)
LC-MS (エレクトロスプレー): m/z: 422 (M+1); Rt = 0.548 分
¹H NMR (400 MHz, MeOH-D4) δ: 8.88(s, 1H), 8.55(d,d, 1H), 8.3(d, 2H), 7.75(d, 2H), 4.2(s, 2H), 3.1-3.7(m, 17H), 3.0(s, 3H), 1.4(d, 6H). Example 47 (General manufacturing method F)
{4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] phenyl}-(4-methylpiperazin-1-yl) -methanone, trihydrochloride:

1- (6-Chloropyridin-3-ylmethyl) -4-isopropylpiperazine (0.5 g, 1.97 mmol) and 4-((4-methyl-piperazin-1-yl) -4- (4,4,5 , 5-tetramethyl- [1,3,2] dioxoborolan-2-yl) phenyl) methanone (0.716 g, 2.2 mmol)) was mixed with the catalyst and reacted in the same manner as Example 18. . The title compound was isolated as white crystals of the trihydrochloride salt. Yield: 1.0 g (96%)
LC-MS (electrospray): m / z: 422 (M + 1); Rt = 0.548 min
¹ H NMR (400 MHz, MeOH-D4) δ: 8.88 (s, 1H), 8.55 (d, d, 1H), 8.3 (d, 2H), 7.75 (d, 2H), 4.2 (s, 2H), 3.1-3.7 (m, 17H), 3.0 (s, 3H), 1.4 (d, 6H).

１-(６-クロロピリジン-３-イルメチル)-４-イソプロピルピペラジン(０.５ｇ、１.９７ｍｍｏｌ)及び４-(Ｎ,Ｎ-ジメチル-アミノスルホニル)フェニルボロン酸(０.４９６ｇ、２.２ｍｍｏｌ))を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を三塩酸塩の白色結晶として単離した。収率：６６０ｍｇ(７１％)
LC-MS (エレクトロスプレー): m/z: 403 (M+1); Rt = 0.947 分
¹H NMR (400 MHz, DMSO-D6) δ: 8.85(s, 1H), 8.3(d, 2H), 8.15(m, 2H), 7.85(d, 2H) 4.45(s, 2H), 3.3-3.65(m, 9H), 2.66(s, 6H), 1.25(d, 6H). Example 48 (General production method F)
4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] -N, N-dimethylbenzenesulfonamide, trihydrochloride:

1- (6-Chloropyridin-3-ylmethyl) -4-isopropylpiperazine (0.5 g, 1.97 mmol) and 4- (N, N-dimethyl-aminosulfonyl) phenylboronic acid (0.496 g, 2.2 mmol) )) Was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the trihydrochloride salt. Yield: 660 mg (71%)
LC-MS (electrospray): m / z: 403 (M + 1); Rt = 0.947 min
¹ H NMR (400 MHz, DMSO-D6) δ: 8.85 (s, 1H), 8.3 (d, 2H), 8.15 (m, 2H), 7.85 (d, 2H) 4.45 (s, 2H), 3.3-3.65 (m, 9H), 2.66 (s, 6H), 1.25 (d, 6H).

１-(６-クロロピリジン-３-イルメチル)-４-イソプロピルピペラジン(０.５ｇ、１.９７ｍｍｏｌ)及び４-(Ｎ-モルホリニル-スルホニル)フェニルボロン酸(０.５８８ｇ、２.２ｍｍｏｌ))を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：５５４ｍｇ(５４％)
LC-MS (エレクトロスプレー): m/z: 445 (M+1); Rt = 0.955 分
¹H NMR (400 MHz, DMSO-D6) δ: 8.9(s, １Ｈ), 8.48(d, 2H), 8.2(d, 2H), 7.88(d, 2H), 4.5(s, 2H), 3.3-3.55(m, 13H), 2.9(m, 4H), 1.28(d, 6H). Example 49 (General manufacturing method F)
4- {4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] benzenesulfonyl} morpholine, dihydrochloride:

1- (6-chloropyridin-3-ylmethyl) -4-isopropylpiperazine (0.5 g, 1.97 mmol) and 4- (N-morpholinyl-sulfonyl) phenylboronic acid (0.588 g, 2.2 mmol)) Mixed with catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 554 mg (54%)
LC-MS (electrospray): m / z: 445 (M + 1); Rt = 0.955 min
¹ H NMR (400 MHz, DMSO-D6) δ: 8.9 (s, 1H), 8.48 (d, 2H), 8.2 (d, 2H), 7.88 (d, 2H), 4.5 (s, 2H), 3.3- 3.55 (m, 13H), 2.9 (m, 4H), 1.28 (d, 6H).

１-(５-ブロモピリジン-２-イルメチル)-４-シクロブチルピペラジン(０.６２、２.０ｍｍｏｌ)及び１-｛２-［４-(４,４,５,５-テトラメチル-１,３,２-ジオキサボロラン-２-イル)フェニル］エチル｝ピロリジン(０.７２３ｇ、２.４ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を三塩酸塩の白色結晶として単離した。収率：３８０ｍｇ(４７％)
LC-MS (エレクトロスプレー): m/z: 405 (M+1); Rt = 0.66 分
¹H NMR (400 MHz, D2O) δ: 8.77 (d, 1H), 7.82 (dd, 1H), 7.50 (d, 2H), 7.44 (d, 1H), 7.32 (d, 2H), 3.72 (s, 2H), 2.90 (m, 2H), 2.75 (m, 3H), 2.61 (m, 8H), 2.42 (m ブロード, 4H), 2.02 (m, 2H), 1.87 (m, 6H), 1.69 (m, 2H). Example 50 (General production method F)
1-cyclobutyl-4- {5- [4- (2-pyrrolidin-1-ylethyl) phenyl] pyridin-2-ylmethyl} piperazine, trihydrochloride:

1- (5-Bromopyridin-2-ylmethyl) -4-cyclobutylpiperazine (0.62, 2.0 mmol) and 1- {2- [4- (4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl) phenyl] ethyl} pyrrolidine (0.723 g, 2.4 mmol) was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the trihydrochloride salt. Yield: 380 mg (47%)
LC-MS (electrospray): m / z: 405 (M + 1); Rt = 0.66 min
¹ H NMR (400 MHz, D2O) δ: 8.77 (d, 1H), 7.82 (dd, 1H), 7.50 (d, 2H), 7.44 (d, 1H), 7.32 (d, 2H), 3.72 (s, 2H), 2.90 (m, 2H), 2.75 (m, 3H), 2.61 (m, 8H), 2.42 (m broad, 4H), 2.02 (m, 2H), 1.87 (m, 6H), 1.69 (m, 2H).

１-(５-ブロモピリジン-２-イルメチル)-４-イソプロピルピペラジン(０.６２、２.０ｍｍｏｌ)及び１-｛２-［４-(４,４,５,５-テトラメチル-１,３,２-ジオキサボロラン-２-イル)フェニル］エチル｝ピロリジン(０.７２３ｇ、２.４ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を三塩酸塩の白色結晶として単離した。収率：３５２ｍｇ(４５％)
LC-MS (エレクトロスプレー): m/z: 393 (M+1); Rt = 0.63 分
¹H NMR (400 MHz, D2O) δ: 8.87 (d, 1H), 8.61 (dd, 1H), 7.92 (d, 1H), 7.65 (d, 2H), 7.42 (d, 2H), 4.09 (s, 2H), 3.56 (m, 2H), 3.46 (m, 4H), 3.19 (m, 5H), 3.05 (m, 4H), 2.76 (m, 2H), 2.03 (m, 2H), 1.87 (m, 2H), 1.25 (d, 6H). Example 51 (General manufacturing method F)
1-isopropyl-4- {5- [4- (2-pyrrolidin-1-ylethyl) phenyl] pyridin-2-ylmethyl} piperazine, trihydrochloride:

1- (5-Bromopyridin-2-ylmethyl) -4-isopropylpiperazine (0.62, 2.0 mmol) and 1- {2- [4- (4,4,5,5-tetramethyl-1,3) , 2-Dioxaborolan-2-yl) phenyl] ethyl} pyrrolidine (0.723 g, 2.4 mmol) was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the trihydrochloride salt. Yield: 352 mg (45%)
LC-MS (electrospray): m / z: 393 (M + 1); Rt = 0.63 min
¹ H NMR (400 MHz, D2O) δ: 8.87 (d, 1H), 8.61 (dd, 1H), 7.92 (d, 1H), 7.65 (d, 2H), 7.42 (d, 2H), 4.09 (s, 2H), 3.56 (m, 2H), 3.46 (m, 4H), 3.19 (m, 5H), 3.05 (m, 4H), 2.76 (m, 2H), 2.03 (m, 2H), 1.87 (m, 2H ), 1.25 (d, 6H).

１-(５-ブロモピリジン-２-イルメチル)-４-シクロブチルピペラジン(０.６２,２.０ｍｍｏｌ)及び１-｛２-［４-(４,４,５,５-テトラメチル-１,３,２-ジオキサボロラン-２-イル)フェニル］メチル｝ピロリジン (０.７２３ｇ、２.４ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を三塩酸塩の白色結晶として単離した。収率：３９１ｍｇ(４８％)
LC-MS (エレクトロスプレー): m/z: 391 (M+1); Rt = 0.65 分
¹H NMR (400 MHz, D2O) δ: 8.69 (d, 1H), 8.61 (dd, 1H), 7.93 (d, 1H), 7.72 (d, 2H), 7.56 (d, 2H), 4.10 (s, 2H), 3.63 (m, 1H), 3.42 (m, ブロード, 2H), 3.10 (m, ブロード, 2H), 2.97 (m,ブロード, 2H), 2.73 (m,ブロード,2H), 2.22 (m, 2H), 2.08 (m, 2H), 1.74 (m, 2H). Example 52 (General production method F)
1-cyclobutyl-4- [5- (4-pyrrolidin-1-ylmethylphenyl) pyridin-2-ylmethyl] piperazine, trihydrochloride:

1- (5-Bromopyridin-2-ylmethyl) -4-cyclobutylpiperazine (0.62, 2.0 mmol) and 1- {2- [4- (4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl) phenyl] methyl} pyrrolidine (0.723 g, 2.4 mmol) was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the trihydrochloride salt. Yield: 391 mg (48%)
LC-MS (electrospray): m / z: 391 (M + 1); Rt = 0.65 min
¹ H NMR (400 MHz, D2O) δ: 8.69 (d, 1H), 8.61 (dd, 1H), 7.93 (d, 1H), 7.72 (d, 2H), 7.56 (d, 2H), 4.10 (s, 2H), 3.63 (m, 1H), 3.42 (m, Broad, 2H), 3.10 (m, Broad, 2H), 2.97 (m, Broad, 2H), 2.73 (m, Broad, 2H), 2.22 (m, 2H), 2.08 (m, 2H), 1.74 (m, 2H).

１-(５-ブロモピリジン-２-イルメチル)-４-シクロブチルピペラジン(１.１６３、３.７５ｍｍｏｌ)及び４-シアノフェニル-ボロン酸(０.８２ｇ、５.６ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を遊離アミンの白色結晶として単離した。収率：４６７ｍｇ(４４％)
LC-MS (エレクトロスプレー): m/z: 333 (M+1); Rt = 0.91 分
¹H NMR (400 MHz, CDCl₃) δ: 8.81 (d, 1H), 7.86 (dd, 1H), 7.77 (d, 2H), 7.68 (d, 2H), 7.50 (d, 1H), 3.77 s, 2H), 2.86 (m, 1H), 2.68 (m, ブロード, 4H), 2.55 (m, ブロード, 4H), 2.05 (m, 4H), 1.73 (m, 2H). Example 53 (General manufacturing method F)
4- [6- (4-Cyclobutylpiperazin-1-ylmethyl) pyridin-3-yl] benzonitrile:

1- (5-Bromopyridin-2-ylmethyl) -4-cyclobutylpiperazine (1.163, 3.75 mmol) and 4-cyanophenyl-boronic acid (0.82 g, 5.6 mmol) were mixed with the catalyst, The reaction was then carried out in the same manner as in Example 18. The title compound was isolated as white crystals of the free amine. Yield: 467 mg (44%)
LC-MS (electrospray): m / z: 333 (M + 1); Rt = 0.91 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.81 (d, 1H), 7.86 (dd, 1H), 7.77 (d, 2H), 7.68 (d, 2H), 7.50 (d, 1H), 3.77 s, 2H), 2.86 (m, 1H), 2.68 (m, Broad, 4H), 2.55 (m, Broad, 4H), 2.05 (m, 4H), 1.73 (m, 2H).

１-(５-ブロモピリジン-２-イルメチル)-４-イソプロピルピペラジン(１.１６３、３.７５ｍｍｏｌ)及び４-シアノフェニル-ボロン酸(０.８２ｇ、５.６ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を遊離アミンの白色結晶として単離した。収率：２４１ｍｇ(２０％)
LC-MS (エレクトロスプレー): m/z: 321 (M+1); Rt = 0.86 分
¹H NMR (400 MHz, CDCl₃) δ: 8.80 (d, 1H), 7.85 (dd, 1H), 7.77 (d, 2H), 7.69 (d, 2H), 7.53 (d,1H), 3.74 (s, 2H), 2.68 (m, 1H), 2.61 (s, 8H), 1.06 (d, 6H). Example 54 (General manufacturing method F)
4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridin-3-yl] benzonitrile:

1- (5-Bromopyridin-2-ylmethyl) -4-isopropylpiperazine (1.163, 3.75 mmol) and 4-cyanophenyl-boronic acid (0.82 g, 5.6 mmol) are mixed with the catalyst, and The reaction was carried out in the same manner as in Example 18. The title compound was isolated as white crystals of the free amine. Yield: 241 mg (20%)
LC-MS (electrospray): m / z: 321 (M + 1); Rt = 0.86 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.80 (d, 1H), 7.85 (dd, 1H), 7.77 (d, 2H), 7.69 (d, 2H), 7.53 (d, 1H), 3.74 (s , 2H), 2.68 (m, 1H), 2.61 (s, 8H), 1.06 (d, 6H).

４-［６-(４-シクロブチルピペラジン-１-イルメチル)ピリジン-３-イル］ベンゾニトリル(０.０６６ｇ、０.２ｍｍｏｌ)をＤＣＭ(１ｍＬ)中に溶解した。ＤＩＢＡＬ１Ｍを含むＴＨＦ(０.２ｍＬ)を加えた。反応混合液を室温で１時間撹拌した。ＬＣ-ＭＳは生成物を示さなかった。反応混合液を-２０℃で３日間貯蔵した。反応混合液にＤＣＭ(５ｍｌ)及び冷ＮＨ₄Ｃｌ_aqを加えた。ＤＣＭ相を水(５ｍｌ)及び塩類溶液(５ｍｌ)で洗浄し、ＭｇＳＯ₄で乾燥し、ろ過し、そして蒸発させて、標題の化合物を遊離塩基として与えた。３４.５ｍｇ(５１％)。
LC-MS(エレクトロスプレー):m/z: 336.7 (M+1); Rt = 0.84 分 Example 55 (General manufacturing method F)
4- [6- (4-Cyclobutylpiperazin-1-ylmethyl) pyridin-3-yl] benzaldehyde:

4- [6- (4-Cyclobutylpiperazin-1-ylmethyl) pyridin-3-yl] benzonitrile (0.066 g, 0.2 mmol) was dissolved in DCM (1 mL). DIBAL 1M in THF (0.2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed no product. The reaction mixture was stored at −20 ° C. for 3 days. To the reaction mixture was added DCM (5 ml) and cold NH ₄ Cl _aq . The DCM phase was washed with water (5 ml) and brine (5 ml), dried over MgSO ₄ , filtered and evaporated to give the title compound as the free base. 34.5 mg (51%).
LC-MS (electrospray): m / z: 336.7 (M + 1); Rt = 0.84 min

１-(６-クロロピリジン-３-イルメチル)-４-イソプロピルピペラジン(０.５ｇ、１.９７ｍｍｏｌ)及びＮ,Ｎ-ジメチル-ベンズアミド-４-ボロン酸(０.４１８ｇ、２.２ｍｍｏｌ))を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：６３７ｍｇ(７４％)
LC-MS (エレクトロスプレー): m/z: 367 (M+1); Rt = 0.723 分
¹H NMR (400 MHz, MeOH-D4) δ: 9.2(s, 1H), 8.9(d,d, 1H), 8.5(d, 1H), 8.1 (d, 2H), 7.7(d, 2H), 4.65(s, 2H), 3.5-3.8(m, 9H), 3.15(s, 3H), 3.05(s, 3H), 1.45(d, 6H). Example 56 (General manufacturing method F)
4- [5- (4-Isopropylpiperazin-1-ylmethyl) pyridin-2-yl] -N, N-dimethylbenzamide, dihydrochloride:

1- (6-chloropyridin-3-ylmethyl) -4-isopropylpiperazine (0.5 g, 1.97 mmol) and N, N-dimethyl-benzamido-4-boronic acid (0.418 g, 2.2 mmol)) Mixed with catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 637 mg (74%)
LC-MS (electrospray): m / z: 367 (M + 1); Rt = 0.723 min
¹ H NMR (400 MHz, MeOH-D4) δ: 9.2 (s, 1H), 8.9 (d, d, 1H), 8.5 (d, 1H), 8.1 (d, 2H), 7.7 (d, 2H), 4.65 (s, 2H), 3.5-3.8 (m, 9H), 3.15 (s, 3H), 3.05 (s, 3H), 1.45 (d, 6H).

ステップ１：
３-クロロ-６-(４-イソプロピルピペラジン-１-イルメチル)ピリダジン,ヒドロクロリド：

５-クロロ-３-クロロメチルピリダジン(３.４６ｇ、２１.２ｍｍｏｌ)及びイソプロピルピペラジン(２.９９ｇ、２３.３ｍｍｏｌ)をＥｔＯＨ(１０ｍｌ)に混合した。撹拌反応混合液を１.５時間加熱した。混合液を冷却し、そして生成物をろ別した。４.２９ｇ(６９％)の白色結晶化合物を塩酸塩として単離した。
¹H NMR (400 MHz,CDCl₃) δ: 7.68 (d, J = 9.10 Hz, 1H), 7.49 (d, J = 9.10 Hz, 1H), 3.86 (s, 2H), 2.65 (septet, J = 6.57 Hz, 1H), 2.56 (s, 8H), 1.05 (d, J = 6.57 Hz, 6H). Example 57 (General manufacturing method F)
4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridazin-3-yl] -N, N-dimethylbenzenesulfonamide, dihydrochloride:

Step 1 :
3-Chloro-6- (4-isopropylpiperazin-1-ylmethyl) pyridazine, hydrochloride:

5-Chloro-3-chloromethylpyridazine (3.46 g, 21.2 mmol) and isopropyl piperazine (2.99 g, 23.3 mmol) were mixed with EtOH (10 ml). The stirred reaction mixture was heated for 1.5 hours. The mixture was cooled and the product was filtered off. 4.29 g (69%) of white crystalline compound was isolated as the hydrochloride salt.
¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.68 (d, J = 9.10 Hz, 1H), 7.49 (d, J = 9.10 Hz, 1H), 3.86 (s, 2H), 2.65 (septet, J = 6.57 Hz, 1H), 2.56 (s, 8H), 1.05 (d, J = 6.57 Hz, 6H).

Step 2 :
3-Chloro-6- (4-isopropylpiperazin-1-ylmethyl) pyridazine, hydrochloride (0.291 g, 1 mmol) and (N, N-dimethylaminosulfonyl) phenylboronic acid (0.274 g, 1.2 mmol) Mixed with catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 226 mg (62%)
LC-MS (electrospray): m / z: 368 (M + 1); Rt = 0.82 min
¹ H NMR (400 MHz1CDCl ₃ ) δ: 8.26 (d, J = 8.59 Hz, 2H), 7.93 (d, J = 8.59 Hz, 2H), 7.89 (d, J = 8.59 Hz, 1H), 7.78 (d, J = 8.59 Hz, 1H), 3.97 (s, 2H), 2.76 (s, 6H), 2.73-2.52 (m, 9H), 1.07 (d, J = 6.57 Hz, 6H).

３-クロロ-６-(４-イソプロピルピペラジン-１-イルメチル)ピリダジン,ヒドロクロリド(０.２９１ｇ、１ｍｍｏｌ)及びＮ,Ｎ-ジメチルベンズアミド-４-ボロン酸(０.２７４ｇ、１.２ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：２２６ｇ(６２％)
LC-MS (エレクトロスプレー): m/z: 368 (M+1); Rt = 0.82 分
¹H NMR (400 MHz, CDCl₃) δ: 8.13 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.58 (d, J = 8.3 Hz, 2H), 3.94 (s, 2H), 3.15 (s, 3H), 3.03 (s, 3H), 2.67 (septet, J = 6.4 Hz, 1H), 2.60 (br.s, 8H), 1.06 (d, J = 6.4 Hz, 6H). Example 58 (General manufacturing method F)
4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridazin-3-yl] -N, N-dimethylbenzamide, dihydrochloride:

Catalyzed 3-chloro-6- (4-isopropylpiperazin-1-ylmethyl) pyridazine, hydrochloride (0.291 g, 1 mmol) and N, N-dimethylbenzamido-4-boronic acid (0.274 g, 1.2 mmol) And reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 226 g (62%)
LC-MS (electrospray): m / z: 368 (M + 1); Rt = 0.82 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.13 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.58 ( d, J = 8.3 Hz, 2H), 3.94 (s, 2H), 3.15 (s, 3H), 3.03 (s, 3H), 2.67 (septet, J = 6.4 Hz, 1H), 2.60 (br.s, 8H ), 1.06 (d, J = 6.4 Hz, 6H).

３-クロロ-６-(４-イソプロピルピペラジン-１-イルメチル)ピリダジン,ヒドロクロリド(０.２９１ｇ、１ｍｍｏｌ)及びＮ-モルホリニル-１-カルボニルフェニル-４-ボロン酸(０.２９１ｇ、１.２ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を三塩酸塩の白色結晶として単離した。収率：２３０ｍｇ(４４％)
LC-MS (エレクトロスプレー): m/z: 410 (M+1); Rt = 0.81 分
¹H NMR (400 MHz1CDCl₃) δ: 8.14 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 8.6 Hz, 2H), 3.95 (s, 2H), 3.82 (br.s, 4H), 3.68 (br.s, 2H), 3.51 (br.s, 2H), 2.67 (septet, J = 6.6 Hz, 1H), 2.62 (br.s, 8H), 1.06 (d, J = 6.6 Hz, 6H). Example 59 (General manufacturing method F)
{4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridazin-3-yl] phenyl} morpholin-4-ylmethanone, trihydrochloride:

3-Chloro-6- (4-isopropylpiperazin-1-ylmethyl) pyridazine, hydrochloride (0.291 g, 1 mmol) and N-morpholinyl-1-carbonylphenyl-4-boronic acid (0.291 g, 1.2 mmol) Was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the trihydrochloride salt. Yield: 230 mg (44%)
LC-MS (electrospray): m / z: 410 (M + 1); Rt = 0.81 min
¹ H NMR (400 MHz1CDCl ₃ ) δ: 8.14 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 8.6 Hz, 2H), 3.95 (s, 2H), 3.82 (br.s, 4H), 3.68 (br.s, 2H), 3.51 (br.s, 2H), 2.67 (septet, J = 6.6 Hz , 1H), 2.62 (br.s, 8H), 1.06 (d, J = 6.6 Hz, 6H).

３-クロロ-６-(４-イソプロピルピペラジン-１-イルメチル)ピリダジン,ヒドロクロリド(０.２９１ｇ、１ｍｍｏｌ)及び４-エチルスルホニルフェニル-４-ボロン酸(０.２５７ｇ、１.２ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：２３６ｍｇ(６１％)
LC-MS (エレクトロスプレー): m/z: 389 (M+1); Rt = 0.87 分
¹H NMR (400 MHz, CDCl₃) δ: 8.29 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 3.97 (s, 2H), 3.18 (q, J = 7.6 Hz, 2H), 2.68 (septet, J = 6.4 Hz, 1H), 2.61 (br.s, 8H), 1.32 (t, J = 7.6 Hz, 3H), 1.06 (d, J = 6.6 Hz, 6H). Example 60 (General manufacturing method F)
3- (4-ethanesulfonylphenyl) -6- (4-isopropylpiperazin-1-ylmethyl) pyridazine, dihydrochloride:

3-chloro-6- (4-isopropylpiperazin-1-ylmethyl) pyridazine, hydrochloride (0.291 g, 1 mmol) and 4-ethylsulfonylphenyl-4-boronic acid (0.257 g, 1.2 mmol) as catalyst Mixed and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 236 mg (61%)
LC-MS (electrospray): m / z: 389 (M + 1); Rt = 0.87 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.29 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.6 Hz, 1H), 7.80 ( d, J = 8.6 Hz, 1H), 3.97 (s, 2H), 3.18 (q, J = 7.6 Hz, 2H), 2.68 (septet, J = 6.4 Hz, 1H), 2.61 (br.s, 8H), 1.32 (t, J = 7.6 Hz, 3H), 1.06 (d, J = 6.6 Hz, 6H).

３-クロロ-６-(４-イソプロピルピペラジン-１-イルメチル)ピリダジン,ヒドロクロリド(０.２９１ｇ,１ｍｍｏｌ)及びＮ-モルホリニル-１-カルボニルフェニル-４-ボロン酸(０.２７９ｇ,１.２ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：２３６ｍｇ(６１％)
LC-MS (エレクトロスプレー): m/z: 408 (M+1); Rt = 1.01 分
¹H NMR (400 MHz, MeOH-D4) δ: 8.69 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H), 8.26 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 4.81 (s, 2H), 3.92 - 3.55 (m, 11H), 3.42 (br.s, 2H), 1.73 (br.s, 4H), 1.58 (br.s, 2H), 1.45 (d, J = 6.6 Hz, 6H). Example 61 (General manufacturing method F)
{4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridazin-3-yl] phenyl} piperidin-1-ylmethanone, dihydrochloride:

3-Chloro-6- (4-isopropylpiperazin-1-ylmethyl) pyridazine, hydrochloride (0.291 g, 1 mmol) and N-morpholinyl-1-carbonylphenyl-4-boronic acid (0.279 g, 1.2 mmol) Was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 236 mg (61%)
LC-MS (electrospray): m / z: 408 (M + 1); Rt = 1.01 min
¹ H NMR (400 MHz, MeOH-D4) δ: 8.69 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H), 8.26 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 4.81 (s, 2H), 3.92-3.55 (m, 11H), 3.42 (br.s, 2H), 1.73 (br.s, 4H), 1.58 (br.s , 2H), 1.45 (d, J = 6.6 Hz, 6H).

３-クロロ-６-(４-イソプロピルピペラジン-１-イルメチル)ピリダジン,ヒドロクロリド(０.２９１ｇ、１ｍｍｏｌ)及び４-((４-メチルピペラジン-１-イル)-４-(４,４,５,５-テトラメチル-［１,３,２］ジオキソボロラン-２-イル)フェニル)メタノン(０.３９６ｇ、１.２ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を二塩酸塩の白色結晶として単離した。収率：２７１ｍｇ(５１％)
LC-MS (エレクトロスプレー): m/z: 423 (M+1); Rt = 0.59 分
¹H NMR (400 MHz, MeOH-D4) δ: 8.47 (d, J = 9.1 Hz, 1H), 8.27 (d, J = 8.6 Hz, 2H), 8.16 (d, J = 9.1 Hz, 1H), 7.74 (d, J = 8.6 Hz, 2H), 4.51 (s, 2H), 3.72 - 3.18 (m, 17H), 2.98 (s, 3H), 1.43 (d, J = 6.6 Hz, 6H). Example 62 (General Production Method F)
{4- [6- (4-Isopropylpiperazin-1-ylmethyl) pyridazin-3-yl] phenyl}-(4-methylpiperazin-1-yl) -methanone, dihydrochloride:

3-Chloro-6- (4-isopropylpiperazin-1-ylmethyl) pyridazine, hydrochloride (0.291 g, 1 mmol) and 4-((4-methylpiperazin-1-yl) -4- (4,4,5 , 5-Tetramethyl- [1,3,2] dioxoborolan-2-yl) phenyl) methanone (0.396 g, 1.2 mmol) was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the dihydrochloride salt. Yield: 271 mg (51%)
LC-MS (electrospray): m / z: 423 (M + 1); Rt = 0.59 min
¹ H NMR (400 MHz, MeOH-D4) δ: 8.47 (d, J = 9.1 Hz, 1H), 8.27 (d, J = 8.6 Hz, 2H), 8.16 (d, J = 9.1 Hz, 1H), 7.74 (d, J = 8.6 Hz, 2H), 4.51 (s, 2H), 3.72-3.18 (m, 17H), 2.98 (s, 3H), 1.43 (d, J = 6.6 Hz, 6H).

１-(５-ブロモピリジン-２-イルメチル)-４-イソプロピルピペラジン(０.６２、２.０ｍｍｏｌ)及び１-｛２-［４-(４,４,５,５-テトラメチル-１,３,２-ジオキサボロラン-２-イル)フェニル］メチル｝ピロリジン(０.７２３ｇ、２.４ｍｍｏｌ)を触媒と混合し、そして実施例１８と同じ様式で反応させた。標題の化合物を三塩酸塩の白色結晶として単離した。収率：４５３ｍｇ(４６％)
LC-MS (エレクトロスプレー): m/z: 379.8 (M+1); Rt = 0.62 分
¹H NMR (400 MHz, CDCl₃) δ: 8.79 (d, 1H), 7.83 (d,d, 1H), 7.53 (d, 2H), 7.45 (m, 3H), 3.72 (s, 2H), 3.67 (s, 2H), 2.66 (m, 1H), 2.60 (m, 6H), 2.54 (m, 6H), 1.80 (m, 4H), 1.06 (d, 6H). Example 63 (General manufacturing method F)
1-isopropyl-4- [5- (4-pyrrolidin-1-ylmethylphenyl) pyridin-2-ylmethyl] piperazine, trihydrochloride:

1- (5-Bromopyridin-2-ylmethyl) -4-isopropylpiperazine (0.62, 2.0 mmol) and 1- {2- [4- (4,4,5,5-tetramethyl-1,3) , 2-Dioxaborolan-2-yl) phenyl] methyl} pyrrolidine (0.723 g, 2.4 mmol) was mixed with the catalyst and reacted in the same manner as Example 18. The title compound was isolated as white crystals of the trihydrochloride salt. Yield: 453 mg (46%)
LC-MS (electrospray): m / z: 379.8 (M + 1); Rt = 0.62 min
¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.79 (d, 1H), 7.83 (d, d, 1H), 7.53 (d, 2H), 7.45 (m, 3H), 3.72 (s, 2H), 3.67 (s, 2H), 2.66 (m, 1H), 2.60 (m, 6H), 2.54 (m, 6H), 1.80 (m, 4H), 1.06 (d, 6H).

Test results

Claims (6)

The following formula I:

{Where,
W, X, Y, and Z are each independently a moiety represented by the formula -C (R ¹ ) = or -N = (that is, nitrogen), provided that 1-2 of W, X, Y, or Z (But not more) must be -N = part,
R ¹ is hydrogen C _1-3 alkyl;
V is -N <(ie nitrogen) or -C <(ie carbon);
A is a bond or an alkylene linker — (CH ₂ ) _n — (where n is 1 to 3), provided that when A is a bond, V must be —CH <. ,
R is ethyl, propyl, branched C _3-6 alkyl or cyclic C _3-8 alkyl;
m is 1, 2 or 3;
n is 1, 2 or 3,
D is halogen, hydroxy, cyano, C _1-6 -alkyl, C _3-8 -cycloalkyl, C _1-6 -alkoxy, — (CH ₂ ) _O — (C═O) _P —NR ² R ³ Optionally substituted heteroaryl or D is hydrogen, halogen, hydroxy, cyano, C _1-6 -alkyl, C _3-8 -cycloalkyl, halo-C _1-6 -alkyl, C _{1- 6} -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkylsulfonyl, C _1-6 -alkylsulfinyl, heterocyclyl, heterocyclyl-C _1-6 -alkyl, heterocyclyl-C _1-6 -alkoxy, heterocyclyl Carbonyl, C _1-6 -alkylcarbonyl, C _1-6 -alkoxycarbonyl, C _1-6 -alkyl-carboxy, cyano-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6- alkoxy -C _1-6 - alkyl, C _1-6 - alkylcarbonylamino C _1-6 - alkylcarbonylamino -C _1-6 - alkyl, arylcarbonyl, arylcarbonylamino -C _1-6 - alkyl, heteroaryl carbonyl amino or heteroarylcarbonylamino -C _1-6 - alkyl, - ( CH ₂ ) _o — (C═O) _p —NR ² R ³ is aryl optionally substituted with one or more groups independently selected from:
o is 0, 1, 2 or 3;
p is 0 or 1;
R ² and R ³ are independently hydrogen, C _1-6 -alkyl or C _3-8 -cycloalkyl; or together with the nitrogen to which R ² and R ³ are bound to form a heterocyclic group Do}
And salts and solvates thereof, preferably pharmaceutically acceptable salts and solvates thereof.   6. A compound according to claim 1 which is a compound generally or specifically mentioned in the description, for example a compound of a specific example, in particular a compound described in any one of examples 1 to 63.   3. A compound according to claim 1 or 2 for use as a medicament.   Use of a compound according to claim 1 or 2 for the manufacture of a pharmaceutical composition for treatment.   4. A method for treating any of the above diseases comprising administering to a subject in need of treatment a therapeutically effective amount of a compound according to any one of claims 1-3.   Any novel feature or combination of features described herein.